Alpha-fluoroalkyl dihydrotetrabenazine imaging agents and probes

ABSTRACT

The present invention provides novel alpha-fluoroalkyl dihydrotetrabenazine compounds I 
     
       
         
         
             
             
         
       
     
     wherein R 1  is a C 1 -C 10  fluorinated aliphatic radical; R 2  is hydrogen or a C 1 -C 10  aliphatic radical; R 3  is hydrogen or a C 1 -C 10  aliphatic radical; and R 4  is a C 1 -C 10  aliphatic radical, a C 3 -C 10  cycloaliphatic radical, or a C 3 -C 10  aromatic radical. The alpha-fluoroalkyl dihydrotetrabenazine compounds are provided in both racemic and enantiomerically enriched forms and may comprise either or both of fluorine-18 and fluorine 19. The alpha-fluoroalkyl dihydrotetrabenazine compounds are believed to possess high affinity for VMAT-2, a biomarker implicated in human diabetes. The alpha-fluoroalkyl dihydrotetrabenazine compounds comprising a fluorine-18 group are useful as PET imaging agents targeting the VMAT-2 biomarker. The non-radiolabled alpha-fluoroalkyl dihydrotetrabenazine compounds are useful as probes for the discovery of PET imaging agents.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a Continuation-in-Part of U.S. patent applications,Ser. Nos. 11/947,215, and 11/947,275 filed on Nov. 29, 2007.

BACKGROUND

This invention relates to alpha-fluoroalkyl compounds related totetrabenazine and dihydrotetrabenazine and intermediates useful in thepreparation of such alpha-fluoroalkyl compounds.

Since first reported on in 1957 (Pletscher, A. (1957) Release of5-hydroxytryptamine by benzoquinolizine derivatives with sedativeaction, Science 126, 507), tetrabenazine and structurally relatedcompounds have been widely investigated, and a number of TBZ compoundsand derivatives of tetrabenazine have shown promise in the treatment ofa variety of conditions affecting human health. For example,dihydrotetrabenazine has been identified as an agent for the treatmentof schizophrenia and other psychoses (See for example WO 2007017654 A1),and tetrabenazine has shown promise as an agent in the treatment ofHuntington's disease (Neurology (2006), 66(3), 366-372). Although mostpreparations used in biological studies of tetrabenazine and itsderivatives have been carried out on racemates, in at least one instancethe biological activity exhibited by enantiomers tested separately washighly differentiated (See Koeppe, R. A. et al. (1999) Assessment ofextrastriatal vesicular monoamine transporter binding site density usingstereoisomers of [11C]dihydrotetrabenazine, J Cereb Blood Flow Metab 19,1376-1384).

More recently, derivatives of 9-desmethyl(±)-dihydrotetrabenazineincorporating a fluorine-18 atom have been shown to be useful as PETimaging agents, Nuclear Medicine and Biology 33 (2006) 685-694. See alsoNuclear Medicine and Biology 34 (2007) 239-246; and Nuclear Medicine andBiology 34 (2007) 233-237.

The present invention provides both a new class of fluorinateddihydrotetrabenazine derivatives and fluorinated dihydrotetrabenazineanalogs, and discloses efficient synthetic methodology which may be usedto prepare such compounds in enantiomerically enriched or racemic forms.The alpha-fluoroalkyl dihydrotetrabenazine compounds provided by thepresent invention are useful as PET imaging agents, probes for thedevelopment of PET imaging agents, and therapeutic agents. In addition,the present invention provides novel synthetic intermediate compositionswhich may be used to prepare either or both enantiomers of the subjectdihydrotetrabenazine derivatives and dihydrotetrabenazine analogs.

BRIEF DESCRIPTION

In one embodiment, the present invention provides an alpha-fluoroalkyldihydrotetrabenazine compound having structure I

wherein R¹ is a C₁-C₁₀ fluorinated aliphatic radical; R² is hydrogen ora C₁-C₁₀ aliphatic radical; R³ is hydrogen or a C₁-C₁₀ aliphaticradical; and R⁴ is a C₁-C₁₀ aliphatic radical, a C₃-C₁₀ cycloaliphaticradical, or a C₃-C₁₀ aromatic radical.

In another embodiment, the present invention provides a PET imagingagent comprising an alpha-fluoroalkyl dihydrotetrabenazine compoundhaving structure I

wherein R¹ is a C₁-C₁₀ fluorinated aliphatic radical; R² is hydrogen ora C₁-C₁₀ aliphatic radical; R³ is hydrogen or a C₁-C₁₀ aliphaticradical; and R⁴ is a C₁-C₁₀ aliphatic radical, a C₃-C₁₀ cycloaliphaticradical, or a C₃-C₁₀ aromatic radical.

DETAILED DESCRIPTION

In the following specification and the claims, which follow, referencewill be made to a number of terms, which shall be defined to have thefollowing meanings.

The singular forms “a”, “an” and “the” include plural referents unlessthe context clearly dictates otherwise.

“Optional” or “optionally” means that the subsequently described eventor circumstance may or may not occur, and that the description includesinstances where the event occurs and instances where it does not.

As used herein, the term “solvent” can refer to a single solvent or amixture of solvents.

Approximating language, as used herein throughout the specification andclaims, may be applied to modify any quantitative representation thatcould permissibly vary without resulting in a change in the basicfunction to which it is related. Accordingly, a value modified by a termor terms, such as “about”, is not to be limited to the precise valuespecified. In some instances, the approximating language may correspondto the precision of an instrument for measuring the value.

As used herein, the term “aromatic radical” refers to an array of atomshaving a valence of at least one comprising at least one aromatic group.The array of atoms having a valence of at least one comprising at leastone aromatic group may include heteroatoms such as nitrogen, sulfur,selenium, silicon and oxygen, or may be composed exclusively of carbonand hydrogen. As used herein, the term “aromatic radical” includes butis not limited to phenyl, pyridyl, furanyl, thienyl, naphthyl,phenylene, and biphenyl radicals. As noted, the aromatic radicalcontains at least one aromatic group. The aromatic group is invariably acyclic structure having 4n+2 “delocalized” electrons where “n” is aninteger equal to 1 or greater, as illustrated by phenyl groups (n=1),thienyl groups (n=1), furanyl groups (n=1), naphthyl groups (n=2),azulenyl groups (n=2), anthraceneyl groups (n=3) and the like. Thearomatic radical may also include nonaromatic components. For example, abenzyl group is an aromatic radical which comprises a phenyl ring (thearomatic group) and a methylene group (the nonaromatic component).Similarly a tetrahydronaphthyl radical is an aromatic radical comprisingan aromatic group (C₆H₃) fused to a nonaromatic component —(CH₂)₄—. Forconvenience, the term “aromatic radical” is defined herein to encompassa wide range of functional groups such as alkyl groups, alkenyl groups,alkynyl groups, haloalkyl groups, haloaromatic groups, conjugated dienylgroups, alcohol groups, ether groups, aldehyde groups, ketone groups,carboxylic acid groups, acyl groups (for example carboxylic acidderivatives such as esters and amides), amine groups, nitro groups, andthe like. For example, the 4-methylphenyl radical is a C₇ aromaticradical comprising a methyl group, the methyl group being a functionalgroup which is an alkyl group. Similarly, the 2-nitrophenyl group is aC₆ aromatic radical comprising a nitro group, the nitro group being afunctional group. Aromatic radicals include halogenated aromaticradicals such as 4-trifluoromethylphenyl,hexafluoroisopropylidenebis(4-phen-1-yloxy) (i.e., —OPhC(CF₃)₂PhO—),4-chloromethylphen-1-yl, 3-trifluorovinyl-2-thienyl,3-trichloromethylphen-1-yl (i.e., 3-CCl₃Ph-),4-(3-bromoprop-1-yl)phen-1-yl (i.e., 4-BrCH₂CH₂CH₂Ph-), and the like.Further examples of aromatic radicals include 4-allyloxyphen-1-oxy,4-aminophen-1-yl (i.e., 4-H₂NPh-), 3-aminocarbonylphen-1-yl (i.e.,NH₂COPh-), 4-benzoylphen-1-yl, dicyanomethylidenebis(4-phen-1-yloxy)(i.e., —OPhC(CN)₂PhO—), 3-methylphen-1-yl, methylenebis(4-phen-1-yloxy)(i.e., —OPhCH₂PhO—), 2-ethylphen-1-yl, phenylethenyl,3-formyl-2-thienyl, 2-hexyl-5-furanyl,hexamethylene-1,6-bis(4-phen-1-yloxy) (i.e., —OPh(CH₂)₆PhO—),4-hydroxymethylphen-1-yl (i.e., 4-HOCH₂Ph-), 4-mercaptomethylphen-1-yl(i.e., 4-HSCH₂Ph-), 4-methylthiophen-1-yl (i.e., 4-CH₃SPh-),3-methoxyphen-1-yl, 2-methoxycarbonylphen-1-yloxy (e.g., methylsalicyl), 2-nitromethylphen-1-yl (i.e., 2-NO₂CH₂Ph),3-trimethylsilylphen-1-yl, 4-t-butyldimethylsilylphenl-1-yl,4-vinylphen-1-yl, vinylidenebis(phenyl), and the like. The term “aC₃-C₁₀ aromatic radical” includes aromatic radicals containing at leastthree but no more than 10 carbon atoms. The aromatic radical1-imidazolyl (C₃H₂N₂—) represents a C₃ aromatic radical. The benzylradical (C₇H₇—) represents a C₇ aromatic radical.

As used herein the term “cycloaliphatic radical” refers to a radicalhaving a valence of at least one, and comprising an array of atoms whichis cyclic but which is not aromatic. As defined herein a “cycloaliphaticradical” does not contain an aromatic group. A “cycloaliphatic radical”may comprise one or more noncyclic components. For example, acyclohexylmethyl group (C₆H₁₁CH₂—) is a cycloaliphatic radical whichcomprises a cyclohexyl ring (the array of atoms which is cyclic butwhich is not aromatic) and a methylene group (the noncyclic component).The cycloaliphatic radical may include heteroatoms such as nitrogen,sulfur, selenium, silicon and oxygen, or may be composed exclusively ofcarbon and hydrogen. For convenience, the term “cycloaliphatic radical”is defined herein to encompass a wide range of functional groups such asalkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups,conjugated dienyl groups, alcohol groups, ether groups, aldehyde groups,ketone groups, carboxylic acid groups, acyl groups (for examplecarboxylic acid derivatives such as esters and amides), amine groups,nitro groups, and the like. For example, the 4-methylcyclopent-1-ylradical is a C₆ cycloaliphatic radical comprising a methyl group, themethyl group being a functional group which is an alkyl group.Similarly, the 2-nitrocyclobut-1-yl radical is a C₄ cycloaliphaticradical comprising a nitro group, the nitro group being a functionalgroup. A cycloaliphatic radical may comprise one or more halogen atomswhich may be the same or different. Halogen atoms include, for example;fluorine, chlorine, bromine, and iodine. Cycloaliphatic radicalscomprising one or more halogen atoms include2-trifluoromethylcyclohex-1-yl, 4-bromodifluoromethylcyclooct-1-yl,2-chlorodifluoromethylcyclohex-1-yl,hexafluoroisopropylidene-2,2-bis(cyclohex-4-yl) (i.e., —C₆H₁₀C(CF₃)₂C₆H₁₀—), 2-chloromethylcyclohex-1-yl, 3-difluoromethylenecyclohex-1-yl,4-trichloromethylcyclohex-1-yloxy,4-bromodichloromethylcyclohex-1-ylthio, 2-bromoethylcyclopent-1-yl,2-bromopropylcyclohex-1-yloxy (e.g., CH₃CHBrCH₂C₆H₁₀O—), and the like.Further examples of cycloaliphatic radicals include4-allyloxycyclohex-1-yl, 4-aminocyclohex-1-yl (i.e., H₂NC₆H₁₀—),4-aminocarbonylcyclopent-1-yl (i.e., NH₂COC₅H₈—),4-acetyloxycyclohex-1-yl, 2,2-dicyanoisopropylidenebis(cyclohex-4-yloxy)(i.e., —OC₆H₁₀C(CN)₂C₆H₁₀O—), 3-methylcyclohex-1-yl,methylenebis(cyclohex-4-yloxy) (i.e., —OC₆H₁₀CH₂C₆H₁₀O—),1-ethylcyclobut-1-yl, cyclopropylethenyl, 3-formyl-2-terahydrofuranyl,2-hexyl-5-tetrahydrofuranyl, hexamethylene-1,6-bis(cyclohex-4-yloxy)(i.e., —O C₆H₁₀(CH₂)₆C₆H₁₀O—), 4-hydroxymethylcyclohex-1-yl (i.e.,4-HOCH₂C₆H₁₀—), 4-mercaptomethylcyclohex-1-yl (i.e., 4-HSCH₂C₆H₁₀—),4-methylthiocyclohex-1-yl (i.e., 4-CH₃SC₆H₁₀—), 4-methoxycyclohex-1-yl,2-methoxycarbonylcyclohex-1-yloxy (2-CH₃OCOC₆H₁₀O—),4-nitromethylcyclohex-1-yl (i.e., NO₂CH₂C₆H₁₀—),3-trimethylsilylcyclohex-1-yl, 2-t-butyldimethylsilylcyclopent-1-yl,4-trimethoxysilylethylcyclohex-1-yl (e.g., (CH₃O)₃SiCH₂CH₂C₆H₁₀—),4-vinylcyclohexen-1-yl, vinylidenebis(cyclohexyl), and the like. Theterm “a C₃-C₁₀ cycloaliphatic radical” includes cycloaliphatic radicalscontaining at least three but no more than 10 carbon atoms. Thecycloaliphatic radical 2-tetrahydrofuranyl (C₄H₇O—) represents a C₄cycloaliphatic radical. The cyclohexylmethyl radical (C₆H₁₁CH₂—)represents a C₇ cycloaliphatic radical.

As used herein the term “aliphatic radical” refers to an organic radicalhaving a valence of at least one consisting of a linear or branchedarray of atoms which is not cyclic. Aliphatic radicals are defined tocomprise at least one carbon atom. The array of atoms comprising thealiphatic radical may include heteroatoms such as nitrogen, sulfur,silicon, selenium and oxygen or may be composed exclusively of carbonand hydrogen. For convenience, the term “aliphatic radical” is definedherein to encompass, as part of the “linear or branched array of atomswhich is not cyclic” a wide range of functional groups such as alkylgroups, alkenyl groups, alkynyl groups, haloalkyl groups, conjugateddienyl groups, alcohol groups, ether groups, aldehyde groups, ketonegroups, carboxylic acid groups, acyl groups (for example carboxylic acidderivatives such as esters and amides), amine groups, nitro groups, andthe like. For example, the 4-methylpent-1-yl radical is a C₆ aliphaticradical comprising a methyl group, the methyl group being a functionalgroup which is an alkyl group. Similarly, the 4-nitrobut-1-yl group is aC₄ aliphatic radical comprising a nitro group, the nitro group being afunctional group. An aliphatic radical may be a haloalkyl group whichcomprises one or more halogen atoms which may be the same or different.Halogen atoms include, for example; fluorine, chlorine, bromine, andiodine. Aliphatic radicals comprising one or more halogen atoms includethe alkyl halides trifluoromethyl, bromodifluoromethyl,chlorodifluoromethyl, hexafluoroisopropylidene, chloromethyl,difluorovinylidene, trichloromethyl, bromodichloromethyl, bromoethyl,2-bromotrimethylene (e.g., —CH₂CHBrCH₂—), and the like. Further examplesof aliphatic radicals include allyl, aminocarbonyl (i.e., —CONH₂),carbonyl, 2,2-dicyanoisopropylidene (i.e., —CH₂C(CN)₂CH₂—), methyl(i.e., —CH₃), methylene (i.e., —CH₂—), ethyl, ethylene, formyl (i.e.,—CHO), hexyl, hexamethylene, hydroxymethyl (i.e., —CH₂OH),mercaptomethyl (i.e., —CH₂SH), methylthio (i.e., —SCH₃),methylthiomethyl (i.e., —CH₂SCH₃), methoxy, methoxycarbonyl (i.e.,CH₃OCO—), nitromethyl (i.e., —CH₂NO₂), thiocarbonyl, trimethylsilyl (i.e., (CH₃)₃Si—), t-butyldimethylsilyl, 3-trimethyoxysilylpropyl (i.e.,(CH₃O)₃SiCH₂CH₂CH₂—), vinyl, vinylidene, and the like. By way of furtherexample, a C₁-C₁₀ aliphatic radical contains at least one but no morethan 10 carbon atoms. A methyl group (i.e., CH₃—) is an example of a C₁aliphatic radical. A decyl group (i.e., CH₃(CH₂)₉—) is an example of aC₁₀ aliphatic radical.

As noted, in one embodiment the present invention provides analpha-fluoroalkyl dihydrotetrabenazine compound having structure I

wherein R¹ is a C₁-C₁₀ fluorinated aliphatic radical; R² is hydrogen ora C₁-C₁₀ aliphatic radical; R³ is hydrogen or a C₁-C₁₀ aliphaticradical; and R⁴ is a C₁-C₁₀ aliphatic radical, a C₃-C₁₀ cycloaliphaticradical, or a C₃-C₁₀ aromatic radical.

The alpha-fluoroalkyl dihydrotetrabenazine compounds I provided by thepresent invention are believed to possess a high affinity for Type 2Vesicular Monoamine Transporters (VMAT-2), a group of biomarkers whichare believed to correlate with diabetes, Parkinson's disease, and otherneurological disorders in human patients. The inventors' recentdiscovery that substitution by fluorine is tolerated with respect toVMAT-2 binding in closely related novel alpha-fluoroalkyl tetrabenazineand dihydrotetrabenazine compounds supports the proposition that thecompounds of present invention may be used as positron emissiontomography (PET) imaging agents in studies targeting the VMAT-2biomarker.

Thus, in one embodiment, the present invention provides radiolabeledalpha-fluoroalkyl dihydrotetrabenazine compounds falling within thescope of generic structure I comprising a fluorine-18 atom. Fluorine-18labeled alpha-fluoroalkyl dihydrotetrabenazine compounds I are suitablefor use as imaging agents for positron emission tomography (PET)screening of human patients for pathological conditions related todiabetes. Positron emission tomography has become a medical imagingtechnique of critical importance to human health.

In an alternate embodiment, the present invention providesalpha-fluoroalkyl dihydrotetrabenazine compounds falling within thescope of either generic structure I and comprising a fluorine-19 atom, astable isotope of fluorine. The alpha-fluoroalkyl compounds comprising afluorine-19 atom are useful in binding studies which allow theidentification of those alpha-fluoroalkyl compounds possessing optimalaffinity for a target biomarker, for example VMAT-2. A substantialbinding affinity of a given fluorine-19 containing alpha-fluoroalkyltetrabenzine or dihydrotetrabenazine compound for a target biomarkersuch as VMAT-2 is a reliable predictor of utility in PET imaging of thecorresponding fluorine-18 containing alpha-fluoroalkyl compound. Basedon data disclosed herein, alpha-fluoroalkyl dihydrotetrabenazinecompounds I are believed to possess substantial binding affinity for thebiomarker VMAT-2.

Although throughout this disclosure there is considerable focus on humanhealth, the alpha-fluoroalkyl dihydrotetrabenazine compounds provided bythe present invention are expected to be useful in the study andtreatment of a variety of human and animal diseases as imaging agents,as probes for the development of imaging agents, and as therapeuticagents.

As noted the present invention provides novel alpha-fluoroalkyldihydrotetrabenazine compounds I

wherein R¹ is a C₁-C₁₀ fluorinated aliphatic radical; R² is hydrogen ora C₁-C₁₀ aliphatic radical; R³ is hydrogen or a C₁-C₁₀ aliphaticradical; and R⁴ is a C₁-C₁₀ aliphatic radical, a C₃-C₁₀ cycloaliphaticradical, or a C₃-C₁₀ aromatic radical

Alpha-fluoroalkyl dihydrotetrabenazine compounds having structure I areillustrated in Table 1 below.

TABLE 1 Examples of Alpha-Fluoroalkyl Dihydrotetrabenazines HavingStructure I Ring Position (“RP”) Stereochemistry Entry R¹ R² R³ R⁴ RP-2RP-3 RP-12 1a

CH₃ CH₃ Ac R/S R/S R/S 1b

CH₃ CH₃ Ac R R R 1c

CH₃O CH₃O EtCO R/S R/S R/S 1d

CH₃O CH₃O H₂NCO R/S* R R 1e

EtO CH₃O H₂NCO R/S* S S 1f

EtO EtO H₂NCO S S S 1g

CH₃CH₂ CH₃CH₂ BnHNCO R/S R/S R/S 1h

CH₃O CH₃O MeNHCO R R R 1i

CH₃O CH₂CH₃ iPrCO R/S R/S R/S 1j

CH₃O H TMS** R/S R/S R *Diastereomeric mixture with ring position-2being epimeric. **Trimethylsilyl

Structure I represents a genus of alpha-fluoroalkyl dihydrotetrabenazinecompounds which includes the racemic compound 1a (Table 1) having boththe R configuration and S configuration at ring positions-2, 3 and 12.In another embodiment, structure I represents alpha-fluoroalkyldihydrotetrabenazine compound 1b (Table 1) having the R configuration(absolute stereochemistry) at ring positions-2, 3 and 12. In yet anotherembodiment, structure I represents compound 1f (Table 1) having absolutestereochemistry opposite that of compound 1b. Those having ordinaryskill in the art will appreciate that the individual alpha-fluoroalkyldihydrotetrabenazine compounds shown in Table 1 herein are illustrativeof dihydrotetrabenazine (DTBZ) derivatives falling within the scope ofgeneric structure I. Those skilled in the art will appreciate as wellthat alpha-fluoroalkyl dihydrotetrabenazine compounds 1d and 1erepresent diastereomeric mixtures.

As noted, in one embodiment, the present invention provides analpha-fluoroalkyl dihydrotetrabenzine compound having structure I whichmay be a racemic mixture (e.g. compound 1a (Table 1), a singleenantiomer (e.g. compound 1b (Table 1), or a compositionenantiomerically enriched in a single principal component enantiomer.Entries 2a-2c in Table 2 below illustrate alpha-fluoroalkyldihydrotetrabenazine compounds I comprising a principal componentenantiomer and at least one minor component enantiomer.

TABLE 2 Alpha-fluoroalkyl Dihydrotetrabenazine Compounds I Comprising APrincipal Component Enantiomer And At Least One Minor ComponentEnantiomer. Structure of Principal Component Structure of MinorComponent Entry Enantiomer Enantiomer 2a

2b

2c

In Table 2 the alpha-fluoroalkyl dihydrotetrabenazine compositionscomprise a principal component enantiomer and a minor componentenantiomer. In the alpha-fluoroalkyl dihydrotetrabenazine compositionsillustrated in Table 2 the mole percentage of the principal componentenantiomer is given as “mole %” and refers to the mole percentage of theprincipal component enantiomer having the structure shown relative tothe amounts of all other alpha-fluoroalkyl dihydrotetrabenazinecomponents in the composition. For the purposes of this discussion analpha-fluoroalkyl dihydrotetrabenazine is any compound falling withinthe scope of generic structure I. Entry 2a represents analpha-fluoroalkyl dihydrotetrabenazine composition comprising 98 mole %of the R, R, R principal component enantiomer shown and a lesser amountof the S, S, S minor component enantiomer. Entry 2c represents analpha-fluoroalkyl dihydrotetrabenazine composition comprising 88 molepercent of the S, S, S principal component enantiomer having thestructure shown and a lesser amount of the R, R, R minor componentenantiomer. Entry 2b represents a pair of diastereomers comprising theR, S, R-enantiomer shown as the principal component enantiomer, and aminor component S, S, S-enantiomer.

In one embodiment, the present invention provides an alpha-fluoroalkyldihydrotetrabenazine compound represented by structure I which isenantiomerically enriched and is comprised of at least 95 mole percent(mole %) of an enantiomer having the R configuration at ringposition-12.

In another embodiment, the present invention provides analpha-fluoroalkyl dihydrotetrabenazine compound represented by structureI which is enantiomerically enriched and is comprised of at least 95mole percent (mole %) of an enantiomer having the R configuration atring position-3.

In one embodiment, the present invention provides an alpha-fluoroalkyldihydrotetrabenazine compound having structure I in which thefluorinated aliphatic radical at ring position-3 (—R¹) has asyn-configuration relative to the hydrogen at ring position-12. Theprincipal component enantiomers of Entries 2a-2c of Table 2 illustratealpha-fluoroalkyl dihydrotetrabenazine compounds in which thefluorinated aliphatic moiety at ring position-3 (—R¹) has asyn-configuration relative to the hydrogen at ring position-12.

In one embodiment, the present invention provides an enantiomericallyenriched alpha-fluoroalkyl dihydrotetrabenazine compound comprising aprincipal component enantiomer having structure II

wherein R¹ is a C₁-C₁₀ fluorinated aliphatic radical; R² is hydrogen ora C₁-C₁₀ aliphatic radical; R³ is hydrogen or a C₁-C₁₀ aliphaticradical; and R⁴ is a C₁-C₁₀ aliphatic radical, a C₃-C₁₀ cycloaliphaticradical, or a C₃-C₁₀ aromatic radical.

Principal component enantiomers having structure II are illustrated inTable 3 below.

TABLE 3 Principal Component Enantiomers Having Structure II EntryStructure 3a

3b

3c

In one embodiment, the present invention provides an enantiomericallyenriched alpha-fluoroalkyl dihydrotetrabenazine compound comprising atleast 80 mole percent of an enantiomer having structure II, for examplethe composition comprising the compound of Entry 3a (Table 3) whereinthe R, R, R enantiomer shown represents at least 80 mole percentrelative to the amounts of all other alpha-fluoroalkyldihydrotetrabenazine components in the composition.

In an alternate embodiment, the present invention provides anenantiomerically enriched alpha-fluoroalkyl dihydrotetrabenazinecompound which is comprised of at least 95 mole % of an enantiomerhaving structure II, for example an alpha-fluoroalkyldihydrotetrabenazine composition comprising the compound of Entry 3b(Table 3) wherein the R, R, R enantiomer shown represents at least 95mole percent relative to the amounts of all other alpha-fluoroalkyldihydrotetrabenazine components in the composition.

In one embodiment, the present invention provides an enantiomericallyenriched alpha-fluoroalkyl dihydrotetrabenazine compound comprising aprincipal component enantiomer having structure II wherein R¹ is aC₅-C₁₀ fluorinated aliphatic radical; and R² and R³ are methoxy groupsand which are illustrated in Table 4 below.

TABLE 4 Principal Component Enantiomers Having Structure II Wherein R¹Is A C₅-C₁₀ Fluorinated Aliphatic Radical And R² And R³ Are MethoxyGroups Entry Structure 4a

4b

4c

4d

In one embodiment, the present invention provides an enantiomericallyenriched alpha-fluoroalkyl dihydrotetrabenazine compound comprising aprincipal component enantiomer having structure III

wherein R¹ is a C₁-C₁₀ fluorinated aliphatic radical; R² is hydrogen ora C₁-C₁₀ aliphatic radical; R³ is hydrogen or a C₁-C₁₀ aliphaticradical; and R⁴ is a C₁-C₁₀ aliphatic radical, a C₃-C₁₀ cycloaliphaticradical, or a C₃-C₁₀ aromatic radical.

Principal component enantiomers having structure III are illustrated inTable 5 below.

TABLE 5 Principal Component Enantiomers Having Structure III EntryStructure 5a

5b

5c

In one embodiment, the present invention provides an enantiomericallyenriched alpha-fluoroalkyl dihydrotetrabenazine compound comprising atleast 80 mole percent of an enantiomer having structure III, for examplean alpha-fluoroalkyl dihydrotetrabenazine composition comprising thecompound of Entry 5a (Table 5) wherein the S, S, S enantiomer shownrepresents at least 80 mole percent relative to the amounts of all otheralpha-fluoroalkyl dihydrotetrabenazine components in the composition. Inanother embodiment, the present invention provides an enantiomericallyenriched alpha-fluoroalkyl dihydrotetrabenazine compound comprising atleast 95 mole percent of an enantiomer having structure III, for examplean alpha-fluoroalkyl dihydrotetrabenazine composition comprising thecompound of Entry 5b (Table 5) wherein the S, S, S enantiomer shownrepresents at least 95 mole percent relative to the amounts of all otheralpha-fluoroalkyl dihydrotetrabenazine components in the composition.

In another embodiment, the present invention provides anenantiomerically enriched alpha-fluoroalkyl dihydrotetrabenazinecompound comprising a principal component enantiomer having structureIII wherein R¹ is a C₅-C₁₀ fluorinated aliphatic radical; and R² and R³are methoxy groups, and which are illustrated in Table 6 below.

TABLE 6 Principal Component Enantiomers Having Structure III Wherein R¹Is A C₅-C₁₀ Fluorinated Aliphatic Radical; And R² And R³ Are MethoxyGroups Entry Structure 6a

6b

6c

6d

The alpha-fluoroalkyl dihydrotetrabenazine compounds provided by thepresent invention are at times herein referred to collectively as“alpha-fluoroalkyl compounds” and comprise a derivitized OH group atring position-3. As will be clear to one of ordinary skill in the art,the term “alpha-fluoroalkyl” refers to the group R¹ of structures I-IIIwhich represents a C₁-C₁₀ aliphatic radical and is not restricted to theordinary meaning of the term “alkyl”. Thus although the termalpha-fluoroalkyl dihydrotetrabenazine is used extensively herein forconvenience and means a dihydrotetrabenazine compound comprising aC₁-C₁₀ fluorinated aliphatic radical at ring position-3.

As noted, the alpha-fluoroalkyl dihydrotetrabenazine compounds I, II,and III provided by the present invention may comprise a fluorine-18atom in the fluorinated aliphatic moiety —R¹. In various embodimentssuch alpha-fluoroalkyl compounds comprising a fluorine-18 atom areuseful as PET imaging agents. Thus, in one embodiment, the presentinvention provides a PET imaging agent comprising an alpha-fluoroalkyldihydrotetrabenazine compound having structure I

wherein R¹ is a C₁-C₁₀ fluorinated aliphatic radical comprising at leastone fluorine-18 atom; R² is hydrogen or a C₁-C₁₀ aliphatic radical; R³is hydrogen or a C₁-C₁₀ aliphatic radical; and R⁴ is a C₁-C₁₀ aliphaticradical, a C₃-C₁₀ cycloaliphatic radical, or a C₃-C₁₀ aromatic radical.

In another embodiment, the present invention provides a PET imagingagent comprising an enantiomerically enriched alpha-fluoroalkyldihydrotetrabenazine compound comprising a principal componentenantiomer having structure II

wherein R¹ is a C₁-C₁₀ fluorinated aliphatic radical comprising at leastone fluorine-18 atom; R² is hydrogen or a C₁-C₁₀ aliphatic radical; R³is hydrogen or a C₁-C₁₀ aliphatic radical; and R⁴ is a C₁-C₁₀ aliphaticradical, a C₃-C₁₀ cycloaliphatic radical, or a C₃-C₁₀ aromatic radical.

In yet another embodiment, the present invention provides a PET imagingagent comprising an enantiomerically enriched alpha-fluoroalkyldihydrotetrabenazine compound comprising a principal componentenantiomer having structure III

wherein R¹ is a C₁-C₁₀ fluorinated aliphatic radical comprising at leastone fluorine-18 atom; R² is hydrogen or a C₁-C₁₀ aliphatic radical; R³is hydrogen or a C₁-C₁₀ aliphatic radical; and R⁴ is a C₁-C₁₀ aliphaticradical, a C₃-C₁₀ cycloaliphatic radical, or a C₃-C₁₀ aromatic radical.

In another embodiment, the present invention provides a PET imagingagent comprising an enantiomerically enriched alpha-fluoroalkyldihydrotetrabenazine compound having structure I, wherein R¹ is a C₅-C₁₀fluoraliphatic radical comprising at least one fluorine-18 atom; and R²and R³ are methoxy groups.

The term “PET imaging agent” as used herein refers to a compositioncomprising a fluorine-18 labeled alpha-fluoroalkyl dihydrotetrabenazinecompound which may be administered to a patient in order to perform aPET scan. Typically, the imaging agent is presented to the patient inthe form of an aqueous formulation containing a sufficient amount offluorine-18 labeled alpha-fluoroalkyl dihydrotetrabenazine compound toconduct the PET scan. Typically, the amount of fluorine-18 labeledalpha-fluoroalkyl dihydrotetrabenazine compound presented to a patientcorresponds to a weight of the fluorine-18 labeled alpha-fluoroalkylcompound on the order of nanograms. In reference to the relative amountsof non-radioactive fluorine-19 containing alpha-fluoroalkyl compoundpresent in the PET imaging agent presented to a patient, the PET imagingagent typically has a specific activity in a range from about 0.01 toabout 10 percent. In one embodiment, the PET imaging agent has aspecific activity in a range from about 0.01 to about 5 percent. Inanother embodiment, the PET imaging agent has a specific activity in arange from about 0.01 to about 1 percent.

The aqueous formulation containing the fluorine-18 alpha-fluoroalkyldihydrotetrabenazine compound is typically administered intravenouslyand may contain various agents which promote the dispersal of the PETimaging agent in water. In one embodiment, the PET imagining agent maybe administered to a patient in an aqueous formulation comprisingethanol and the fluorine-18 labeled alpha-fluoroalkyl compound. In analternate embodiment, the PET imagining agent may be administered to apatient as an aqueous formulation comprising dextrose and thefluorine-18 labeled alpha-fluoroalkyl compound. In yet anotherembodiment, the PET imagining agent may be administered to a patient asan aqueous formulation comprising saline and the fluorine-18 labeledalpha-fluoroalkyl compound.

In addition to being useful as PET imaging agents and as probes fordetermining the suitability of a given alpha-fluoroalkyl compound foruse as a PET imaging agent, the alpha-fluoroalkyl compounds provided bythe present invention are believed to possess therapeutic utility in thetreatment of diseases such as schizophrenia, Huntington's disease, andParkinson's disease. Thus, in one embodiment, the present inventionprovides an alpha-fluoroalkyl dihydrotetrabenazine compound havingstructure I which is useful in treating a pathological condition in apatient. In various other embodiments, the present invention providesenantiomerically enriched alpha-fluoroalkyl dihydrotetrabenazinecompounds II and III, and mixtures thereof, which are useful in treatinga pathological condition in a patient. Typically the amount of thealpha-fluoroalkyl compound administered to a patient in a given dose ison the order of milligrams.

Those skilled in the art will appreciate that alpha-fluoroalkylcompounds such as alpha-fluoroalkyl compounds falling within the scopeof generic structure I may under a variety of conditions form saltswhich are useful as PET imaging agents, probes for the discovery anddevelopment of imaging agents, and/or therapeutic agents. Thus, thepresent invention provides a host of novel and useful alpha-fluoroalkylcompounds and their salts. For example, in one particular embodiment,the present invention provides the hydrochloride salts of the novelalpha-fluoroalkyl compounds, for example the hydrochloride salt of thecompound of Entry 4a of Table 4.

The alpha-fluoroalkyl dihydrotetrabenazine compounds I of the presentinvention may be prepared by a variety of methods including thoseprovided in the experimental section of this disclosure. In oneembodiment, the alpha-fluoroalkyl dihydrotetrabenazine compound I isprepared by reaction of nucleophilic fluoride ion or an electrophilicfluorinating agent with a fluorophilic tetrabenazine- ordihydrotetrabenazine compound having structure IV

wherein Q is a carbonyl group, a protected carbonyl group, a hydroxymethine group, or a protected hydroxy methine group; R¹ is a C₁-C₂₀aliphatic, C₂-C₂₀ cycloaliphatic, or C₂-C₂₀ aromatic radical comprisingat least one functional group susceptible to reaction with nucleophilicfluoride ion or an electrophilic fluorinating agent; R² is hydrogen or aC₁-C₁₀ aliphatic radical; and R³ is hydrogen or a C₁-C₁₀ aliphaticradical. Where Q is a carbonyl group, a protected carbonyl group, or ahydroxy methine group, access to the alpha-fluoroalkyldihydrotetrabenazine compounds of the present invention may involveadditional chemical transformation (e.g. acetylation) following reactionof compound IV with nucleophilic fluoride ion or an electrophilicfluorinating agent.

Fluorophilic tetrabenazine- and dihydrotetrabenazine compounds havingstructure IV are illustrated in Table 7 below.

TABLE 7 Examples of Fluorophilic Tetrabenazine- and DihydrotetrabenazineCompounds Having Structure IV Ring Position (“RP”) Stereochemistry EntryR¹ R² R³ Q RP-2 RP-3 RP-12 7a

CH₃ CH₃

R/S R/S R/S 7b

CH₃ CH₃

R R R 7c

CH₃O CH₃O

— R/S R/S 7d

CH₃O CH₃O

R R R 7e

EtO CH₃O

— S S 7f

EtO EtO

S S S 7g

CH₃CH₂ CH₃CH₂

R/S R/S R/S 7h

CH₃O CH₃O

R R R 7i CH₃O CH₂CH₃

R/S R/S R/S 7j

CH₃O H

R/S R/S R 7k

CH₃O CH₃O

R R R 7l

CH₃O CH₃O

— S S

As provided for in generic structure IV, the fluorophilic tetrabenazine-and dihydrotetrabenazine compounds which may be used to prepare thecompounds of the present invention include compounds which are formallytetrabenazine compounds (i.e., Q is a carbonyl group, for exampleEntries 7c and 7e of Table 7); compounds which are dihydrotetrabenazinecompounds bearing a free hydroxy group at ring (i.e., Q is a hydroxymethine group, for example Entry 7b of Table 7); “protected”tetrabenazine compounds (i.e., Q is a protected carbonyl group, forexample Q is ethylene ketal group as found in tetrabenazine ketaltosylate 33 of Example 4 herein); or dihydrotetrabenazine compounds notbearing a free hydroxy group at ring position-2 (i.e., Q is a“protected” hydroxy methine group, for example Q is a CHOTHP group as inEntry 7a of Table 7 and in tosylate 34 of Example 5 herein). The term“protected carbonyl group” refers to a carbonyl group equivalent,usually a carbonyl group which has been transformed into a functionalgroup such as a ketal, thioketal, or dithioketal group; and the term“protected hydroxy methine group” refers to a hydroxy methine groupequivalent, usually a hydroxy methine group which has been transformedinto a functional group such as a tetrahydropyranyl (THP) ether group, amethoxymethyl ether group (MOM group), a methoxyethoxyether group (MEMgroup), a methylthiomethyl ether group, a benzyl ether group, ap-methoxybenzyl ether group, a pivaloyl ester group (OPiv), or anactetyl ester group (OAc). Protection agents which may be used totransform a carbonyl group or a hydroxy methine group into a protectedcarbonyl group or a protected hydroxy methine group are well known inthe art, for example protection agents detailed in Protecting Groups InOrganic Synthesis by James R. Hanson (Blackwell Science, 1999) andGreene's Protective Groups in Organic Synthesis (Wiley-Interscience,2006).

As noted, in one embodiment, the alpha-fluoroalkyl dihydrotetrabenazinecompounds provided by the present invention may be prepared from afluorophilic compound having structure IV, wherein R¹ is a C₁-C₂₀aliphatic radical, a C₂-C₂₀ cycloaliphatic radical, or a C₂-C₂₀ aromaticradical comprising at least one functional group susceptible to reactionwith nucleophilic fluoride ion. In one embodiment, the functional groupsusceptible to reaction with nucleophilic fluoride ion is an aromaticsulfonate ester (e.g. tosylate, benzenesulfonate, naphthalenesulfonate).In an alternate embodiment, the functional group susceptible to reactionwith nucleophilic fluoride ion is an aliphatic sulfonate ester (e.g.methane sulfonate, trifluoromethane sulfonate). In one embodiment, thefunctional group susceptible to reaction with nucleophilic fluoride ionis selected from the group consisting of tosylate, mesylate, andtrifluoromethane sulfonate groups.

In one embodiment, the alpha-fluoroalkyl dihydrotetrabenazine compoundsprovided by the present invention may be prepared from a fluorophiliccompound having structure IV wherein the group R¹ comprises at least onetosylate group susceptible to reaction with nucleophilic fluoride ion.See for example the Entries 7a, 7j and 7k of Table 7. As defined herein,the tosylate group is an aromatic radical and the group R¹ comprisingthe tosylate group is also an aromatic radical. In the compound shown inEntry 7a for example, the group R¹ comprising the tosylate group is a C₉aromatic radical which upon displacement with fluoride ion becomes a C₂fluorinated aliphatic radical.

In an alternate embodiment, alpha-fluoroalkyl dihydrotetrabenazinecompounds provided by the present invention may be prepared from afluorophilic compound having structure IV wherein the group R¹ comprisesat least one mesylate group (methane sulfonate group) susceptible toreaction with nucleophilic fluoride ion. As defined herein, the mesylategroup is an aliphatic radical and the group R¹ comprising the mesylategroup may be an aliphatic, a cycloaliphatic or an aromatic radicaldepending on the overall structure of the group R¹. For example, in afluorophilic compound having structure IV in which R¹ comprises both amesylate group and an epoxy group, the group R¹ may be a cycloaliphaticradical. Alternatively, in a fluorophilic compound having structure IVin which R¹ comprises both a mesylate group and a tosylate group, thegroup R¹ is an aromatic radical. It is helpful to bear in mind that thedefinitions of aliphatic, cycloaliphatic and aromatic radicals providedin this disclosure establish a hierarchy in which aliphatic radicals(non-cyclic arrays of atom(s)) must be free of cycloaliphatic groups (acyclic array of atoms which is not aromatic) and aromatic groups (acyclic array of atoms which is aromatic), cycloaliphatic radicals mustbe free of aromatic groups, and aromatic radicals must simply comprisean aromatic group.

In one embodiment, the alpha-fluoroalkyl dihydrotetrabenazine compoundsprovided by the present invention may be prepared from a fluorophiliccompound having structure IV wherein the group R¹ comprises at least onetrifluoromethane sulfonate (triflate) group susceptible to reaction withnucleophilic fluoride ion. See for example Entry 7b of Table 7.

In an alternate embodiment, the alpha-fluoroalkyl dihydrotetrabenazinecompounds provided by the present invention may be prepared from afluorophilic compound having structure IV wherein the group R¹ comprisesat least one p-nitrobenzoate group susceptible to reaction withnucleophilic fluoride ion. See for example Entry 7c of Table 7.

In one embodiment, the alpha-fluoroalkyl dihydrotetrabenazine compoundsprovided by the present invention may be prepared from a fluorophiliccompound having structure IV wherein the group R¹ comprises at least oneepoxy group susceptible to reaction with nucleophilic fluoride ion. Seefor example Entry 7i of Table 7.

In yet another embodiment, the alpha-fluoroalkyl dihydrotetrabenazinecompounds provided by the present invention may be prepared from afluorophilic compound having structure IV wherein the group R¹ comprisesat least one cyclic sulfate group susceptible to reaction withnucleophilic fluoride ion. See for example Entry 71 of Table 7.

In one embodiment, the alpha-fluoroalkyl dihydrotetrabenazine compoundsprovided by the present invention may be prepared from a fluorophiliccompound having structure IV, wherein R¹ is a C₂-C₂₀ aliphatic radicalcomprising at least one functional group susceptible to reaction with anelectrophilic fluorinating agent, for example fluorine gas, perchlorylfluoride, mercuric fluoride, and phenyl selenenyl fluoride.

Thus in one embodiment, the functional group susceptible to reactionwith an electrophilic fluorinating agent is selected from the groupconsisting of carbon-carbon double bonds and carbon-carbon triple bonds.Entries 7e, 7f, 7g, 7h and 7k of Table 7 illustrate compounds fallingwithin the scope of generic structure IV which are susceptible toreaction with an electrophilic fluorinating agent. Attention is calledto Entry 7k wherein the group R¹ comprises functional groups susceptibleto reaction with an electrophilic fluorinating agent (double bond) andto reaction with nucleophilic fluoride ion (tosylate group). Entry 7k ofTable 7 also features a thioketal carbonyl protecting group. As usedherein a thioketal protecting group comprises both an oxygen and asulfur atom bonded to the “carbonyl carbon” and is distinguished from adithioketal which comprises two sulfur atoms attached to the “carbonylcarbon”.

Fluorophilic tetrabenazine- and dihydrotetrabenazine compounds IV may beprepared in enantiomerically enriched or racemic forms. For example, afluorophilic dihydrotetrabenazine compound IV may be enriched in theR,R,R-enantiomer shown in Entry 7h (a fluorophilic dihydrotetrabenazinecompound) of Table 7. Alternatively, a fluorophilic tetrabenazine- ordihydrotetrabenazine compound IV may be enriched in an enantiomer havingabsolute stereochemistry opposite that of Entry 7d of Table 7, forexample the S,S,S-enantiomer of Entry 7f.

Thus, in one embodiment, the compounds of the present invention may beprepared from an enantiomerically enriched fluorophilic compoundcomprising a principal component enantiomer having structure V

wherein Q is a carbonyl group, a protected carbonyl group, a hydroxymethine group, or a protected hydroxy methine group; R¹ is a C₁-C₂₀aliphatic, C₂-C₂₀ cycloaliphatic, or C₂-C₂₀ aromatic radical comprisingat least one functional group susceptible to reaction with nucleophilicfluoride ion or an electrophilic fluorinating agent; R² is hydrogen or aC₁-C₁₀ aliphatic radical; and R³ is hydrogen or a C₁-C₁₀ aliphaticradical. Principal component enantiomers V are illustrated by Entries7b, 7d, 7h, and 7k of Table 7. Where Q is a carbonyl group, a protectedcarbonyl group, or a hydroxy methine group, access to thealpha-fluoroalkyl dihydrotetrabenazine compounds of the presentinvention may involve additional chemical transformation (e.g.acetylation) following reaction of compound V with nucleophilic fluorideion or an electrophilic fluorinating agent.

In an alternate embodiment, the compounds of the present invention maybe prepared from an enantiomerically enriched fluorophilic compoundcomprising a principal component enantiomer having structure VI

wherein Q is a carbonyl group, a protected carbonyl group, a hydroxymethine group, or a protected hydroxy methine group; R¹ is a C₁-C₂₀aliphatic, C₂-C₂₀ cycloaliphatic, or C₂-C₂₀ aromatic radical comprisingat least one functional group susceptible to reaction with nucleophilicfluoride ion or an electrophilic fluorinating agent; R² is hydrogen or aC₁-C₁₀ aliphatic radical; and R³ is hydrogen or a C₁-C₁₀ aliphaticradical. Principal component enantiomers VI are illustrated by Entries7e and 7f of Table 7. Where Q is a carbonyl group, a protected carbonylgroup, or a hydroxy methine group, access to the alpha-fluoroalkyldihydrotetrabenazine compounds of the present invention may involveadditional chemical transformation (e.g. acetylation) following reactionof compound VI with nucleophilic fluoride ion or an electrophilicfluorinating agent.

Co-pending U.S. patent applications Ser. No. 11/760,359 and Ser. No.11/760,372 filed Jun. 8, 2007 disclose methods for the preparation ofracemic and enantiomerically enriched tetrabenazine- anddihydrotetrabenazine compositions IV which may be used in thepreparation of compounds of the present invention. In addition, theExamples Section of the present disclosure provides detailedexperimental descriptions of the preparation and characterization offluorophilic tetrabenazine- and dihydrotetrabenazine compounds IV andtheir conversion to alpha-fluoroalkyl dihydrotetrabenazine compounds I.

In general, fluorophilic tetrabenazine and dihydrotetrabenazinecompounds IV can be prepared by reacting a nucleophilic alkenyl specieswith an aldehyde compound having structure VII

wherein R² is hydrogen or a C₁-C₁₀ aliphatic radical; and R³ is hydrogenor a C₁-C₁₀ aliphatic radical; and P¹ is a protecting group,to provide an allylic alcohol (See Methods 4, 5, and 6 of the Examplessection), which is then oxidized to provide an enone designated the“first intermediate” (See Methods 7, 8, and 9 of the Examples section),the protecting group P¹ of which is then removed and the resultantdeprotected first intermediate undergoes an amino cyclization reactionto afford the corresponding tetrabenazine compound.

Representative aldehyde compounds encompassed by generic formula VII aregiven in Table 8.

TABLE 8 Representative Aldehyde Compounds Encompassed By Formula VIIRing Position* Compound Stereo- Entry Type chemistry Structure 8a Single“R” enantiomer, “Boc” protecting group P¹ RP-12 “R”

8b Single “S” enantiomer, “Boc” protecting group P¹ RP-12 “S”

8c Enantiomeric ally enriched mixture of “R” and “S” enantiomers,“alloc” protecting group P¹ RP-12 “R/S”

8d Racemic mixture of “R” and “S” enantiomers; “Fmoc” protecting groupP¹ RP-12 “R/S”

8e Racemic mixture of “R” and “S” enantiomers; “Cbz” protecting group P¹RP-12 “R/S”

8f Racemic mixture of “R” and “S” enantiomers; “Teoc” protecting groupP¹ RP-12 “R/S”

8g Single “R” enantiomer, “Boc” protecting group P¹ RP-12 “R”

The preparation of the aldehyde compound featured in Entry 8a of Table 8is described in the Examples section of this disclosure (Methods 1-3).In general, the class of aldehyde compounds represented by structure VIImay be prepared by art recognized methods, for example using themethodology depicted in Scheme 1. Those skilled in the art willappreciate that as depicted in Scheme 1 the protecting group P¹represents a “Boc” protecting group.

Thus, aldehyde compounds VII may be prepared from intermediates preparedusing methodology described by Sasamoto et al. (Journal of the AmericanChemical Society 128, 14010-14011, 2006). Sasamoto et al. disclose thepreparation of enantiomerically enriched tetrahydroquinoline malonatecompounds which may be converted as shown in the present disclosure toaldehyde compound VII by selective hydrolysis of one of the estermoieties of the tetrahydroquinoline malonate and decarboxylationfollowed by reduction of the resultant tetrahydroisoquinoline monoesterto aldehyde compound VII as depicted in Scheme 1.

One of ordinary skill in the art will appreciate that the 2 mole percentDM-SEGPHOS shown in Scheme 1 represents a chiral catalyst responsiblefor the enantiomeric enrichment of the product aldehyde VII, and furtherthat the use of DM-SEGPHOS of opposite chirality as the chiral catalystwill afford a product aldehyde VII enantiomerically enriched in the “S”enantiomer (aldehyde compound VII having the S configuration at ringposition-12 (See for example Entry 8b of Table 8). Suitable chiralcatalysts include those disclosed by Sasamoto et al. (Journal of theAmerican Chemical Society 128, 14010-14011, 2006), for example(S)-Binap, (R)-Binap, (S)-DM-Binap, (R)-DM-Binap, (S)-DM-SEGPHOS, and(R)-DM-SEGPHOS. Typically use of a catalyst consisting of a ligandpossessing a single, for example “S”, configuration producesstereochemically enriched malonate adducts of the opposite “R”configuration and vice versa.

In addition to the use of a chiral catalyst to generate aldehydecompounds VII enriched in a single configuration at ring position-12,there are available a wide variety of methods for the separation ofracemic aldehyde VII into its constituent enantiomers. For example,racemic aldehyde compound VII may be separated into its constituentenantiomers by high performance liquid chromatography (hplc) on a chiralhplc column.

Other methods for producing enantiomerically enriched compositionsprovided by the present invention include conversion of a racemicalpha-fluoroalkyl compound having structure I compound into an adductcomprising a mixture of diastereomers which are then separated byfractional crystallization. For example, a racemic alpha-fluoroalkylcompound having structure I may be reacted with (−)-tartaric acid toform an adduct (ammonium tartarate salt) of the racemicalpha-fluoroalkyl compound, said adduct comprising a mixture ofdiastereomeric ammonium tartarate salts which are then separated byfractional crystallization.

METHODS AND EXAMPLES

The following Examples and Methods are intended only to illustratemethods and embodiments in accordance with the invention, and as suchshould not be construed as imposing limitations upon the claims.

Method 1 Preparation of Protected Diester 2

The dihydroisoquinoline 1 (1.0 eq.) and Boc anhydride (1.5 eq.) weredissolved in CH₂Cl₂ at room temperature to provide a 1.5 M solution withrespect to the dihydroisoquinoline. The mixture was allowed to stir for30 min. Following the allotted time, the reaction mixture was cooled to0° C. and then diisopropylmalonate (1.5 eq.) followed by a pre-chilledsolution of the Pd catalyst (0.008 eq.) in dichloromethane were addedsuccessively to the reaction mixture to provide a final reactionconcentration of 0.84 M with respect to the startingdihydroisoquinoline. The reaction mixture was allowed to continuestirring at ˜2.5° C. for 15 h. Following this time EtOAc and brine wereadded to the reaction mixture. The aqueous layer was extracted withthree portions of EtOAc and the combined organic layers were dried(Na₂SO₄), filtered, and concentrated under reduced pressure to providethe crude product. The crude material was dissolved in a minimal amountof dichloromethane and purified by flash chromatography on SiO₂ (15-30%EtOAc-hexanes, elution was observed at 285 nm and 228 nm). The product 2was a colorless solid that existed as a mixture of rotamers in solutionat room temperature 94%: [α]²⁶ _(D)−69.0 (c 0.21, CHCl₃); ¹H NMR (CDCl₃)δ 0.81-1.02 (m, 6H), 1.06-1.17 (m, 6H), 1.23-1.38 (m, 9H), 2.51-2.63 (m,1H), 2.64-2.77 (m, 1H), 3.20-3.29 (m, 0.6H), 3.32-3.41 (m, 0.4H),3.51-3.58 (m, 1H), 3.62-3.70 (m, 6H), 3.70-3.76 (m, 0.4H), 3.91-4.01 (m,0.6H), 4.65-4.82 (m, 1H), 4.83-4.98 (m, 1H), 5.71 (apparent d, J=5.7 Hz,0.6H), 5.78 (apparent d, J=7.9 Hz, 0.4H), 6.42-6.49 (m, 1H), 6.77 (s,0.6H), 6.81 (s, 0.4H); ¹³C NMR (CDCl₃) δ 21.02, 21.09, 21.18, 21.32,27.24, 27.95, 28.02, 37.60, 39.34, 52.11, 52.83, 55.48, 55.52, 59.28,60.08, 68.58, 68.76, 68.82, 79.46, 80.03, 110.09, 110.73, 111.13,126.11, 126.18, 126.37, 127.07, 146.81, 146.87, 147.93, 153.86, 154.30,166.29, 166.78, 166.94, 167.06.

Method 2 Selective Hydrolysis and Decarboxylation of Protected Diester 2

The starting material 2 was taken up in isopropanol to provide a 0.2 Msolution of 2. To this solution was added 1M aqueous NaOH solutionbringing the final concentration of the reaction mixture to 0.1M withrespect to the malonate 2. The reaction mixture was heated to andmaintained 70° C. for 22 min. (timing was started when the temperatureof the reaction mixture temp exceeded 65° C.). Following the allottedtime the reaction mixture was quickly cooled to 0° C. The reactionmixture carefully acidified with 2M aqueous HCl and extracted with threeportions of dichloromethane. The combined organic extracts dried(Na₂SO₄), filtered and concentrated under reduced pressure. The isolatedmaterial was taken up in THF to provide a 0.1 M solution (based on theoriginal quantity of 2 used in the reaction mixture) and triethylamine(1.0 eq) was added to the reaction mixture at room temperature. Thereaction mixture was heated to its reflux temperature and maintained atthis temperature for 90 min. The reaction mixture was concentrated underreduced pressure, dissolved in a minimal quantity of CH₂Cl₂ and wasimmediately purified by column chromatography on SiO₂ (15-40%EtOAc-hexanes; 40%, the eluant was monitored at 284 nm). The product 3existed as a mixture of rotamers at room temperature and was a colorlessfoam 79%: [α]²⁶ _(D)−82 (c 0.24, CH₂Cl₂); ¹H NMR (CDCl₃) δ 1.19-1.25 (m,6H), 1.43-1.49 (m, 9H), 2.58-2.69 (m, 2H), 2.70-2.77 (m, 1H), 2.78-2.92(m, 1H), 3.13-3.43 (m, 1H), 3.81-3.85 (m, 6H), 3.86-4.01 (m, 1H),4.91-5.05 (m, 1H), 5.38-5.61 (m, 1H), 6.56-6.61 (m, 1H), 6.64-6.70 (s,1H); ¹³C NMR (CDCl₃) δ 21.75, 21.90, 27.93, 28.08, 28.44, 37.53, 38.75,42.22, 42.81, 51.11, 51.87, 55.92, 56.02, 68.08, 79.74, 80.21, 109.60,109.99, 111.44, 111.54, 126.28, 126.48, 128.54, 128.76, 147.51, 147.97,154.39, 154.51, 170.36, 170.59; LRMS-(ESI+) calcd for (C₂₁H₃₁NO₆+H)[M+H]⁺ 394.22, found 394.16.

Method 3 Preparation of Aldehyde Compound 4

To a 0.12 M solution of the starting monoester (3, 1.0 eq.) in tolueneat −78° C. was added a 1.5 M solution of DiBAl-H in hexanes (1.5 eq.)dropwise via a syringe pump. Following the addition the reaction mixturewas stirred at −78° C. for 2 h. The reaction mixture was quenched by theaddition of EtOAc and was then acidified with saturated aqueous citricacid solution. The reaction mixture was allowed to warm to roomtemperature and continue stirring for 30 min. The phases were separated,and the aqueous layer extracted with three portions of EtOAc. Thecombined organic extracts were washed with two portions of 2 M aqueousHCl solution, brine, dried (MgSO₄), filtered, and concentrated underreduced pressure. The crude product was subjected purification on SiO₂(15-35% EtOAc-hexanes; Elution was observed at 285 nm and 228 nm). Theisolated product aldehyde compound 4 was a colorless foam. The productexisted as a 1:1 mixture of rotamers at room temperature 76%: [α]²⁶_(D)−116 (c 0.26,CH₂Cl₂); ¹H NMR (CDCl₃) δ 1.40 (s, 9H), 2.58 (apparentt, J=3.8 Hz, 0.5H), 2.61 (apparent t, J=3.5 Hz, 0.5H), 2.68-2.88 (m,3H), 3.02-3.27 (m, 1H), 3.78 (apparent s, 6H), 3.87-3.99 (m, 0.5H),4.08-4.23 (m, 0.5H), 5.37-5.68 (m, 1H), 6.55 (s, 1H), 6.58 (s, 1H), 9.78(s, 1H); ¹³C NMR (CDCl₃) δ 20.90, 28.02, 28.27, 37.23, 38.65, 49.29,49.93, 51.12, 55.83, 55.96, 80.13, 80.64, 109.42, 109.52, 111.52,126.34, 126.51, 127.78, 127.82, 147.72, 147.97, 153.85, 154.62, 200.08,200.33.

Method 4 Reaction of Aldehyde Compound 4 with Nucleophilic AlkenylSpecies Derived from Alkenyl Iodide 5 with to Provide Allylic Alcohol 6

To a neat mixture of the alkenyl iodide 5 (1.0 eq) and the aldehydecompound 4 (1.0 eq.) at room temperature was added 2.65 eq. of chromiumchloride doped with 0.5% NiCl₂ (w/w). The mixture was vortexed for about2 min. to provide a homogeneous, green/grey paste and then stirred undernitrogen for an additional 10 min. after which time anhydrous DMF wasadded to bring the final reaction concentration to 0.36 M. The reactionmixture was deep green in color and was permitted to continue stirringat room temperature for 14 h. Following the allotted time, the reactionmixture was diluted with 1:1 EtOAc-hexanes and an aqueous 0.5 M EDTAsolution (pH 9) was added and the entire mixture was allowed to stir for1.5 h. The aqueous layer was extracted with three portions of EtOAc,dried (MgSO₄), filtered, and the filtrate was concentrated under reducedpressure to provide a green oil. The crude material was subjected tocolumn chromatography on SiO₂ (35% EtOAc-hexanes; elution was observedat 285 nm and 228 nm). The product allylic alcohol 6 was a pale yellowoil isolated in 53% yield as a mixture of diastereomers which was takenon to the next step without additional characterization or analysis.

Method 5 Reaction of Aldehyde Compound 4 with Nucleophilic AlkenylSpecies Derived from Alkenyl Iodide 7 with to Provide Allylic Alcohol 8

To a neat mixture of the alkenyl iodide 7 (1.0 eq) and the aldehydecompound 4 (1.25 eq.) at room temperature was added 2.5 eq. of chromiumchloride doped with 0.5% NiCl₂ (w/w). The mixture was vortexed for about2 min. to provide a homogeneous, green/grey paste and then stirred undernitrogen for an additional 10 min. after which time anhydrous DMF wasadded to bring the final reaction concentration to 0.32 M. The reactionmixture was deep green in color and was permitted to continue stirringat room temperature for 14 h. Following the allotted time, the reactionmixture was diluted with 1:1 EtOAc-hexanes and an aqueous 0.5 M EDTAsolution (pH 9) was added and the entire mixture was allowed to stir for1.5 h. The aqueous layer was extracted with three portions of EtOAc,dried (MgSO₄), filtered, and the filtrate was concentrated under reducedpressure to provide a green oil. The crude material was subjected tocolumn chromatography on SiO₂ (20% EtOAc-hexanes to 35% EtOAc-hexanes;elution was observed at 285 nm and 228 nm). The product allylic alcohol8 was a pale yellow oil isolated in 54% yield as a mixture ofdiastereomers which was taken on to the next step without additionalcharacterization or analysis.

Method 6 Reaction of Aldehyde Compound 4 with Nucleophilic AlkenylSpecies Derived from Alkenyl Iodide 9 with to Provide Allylic Alcohol 10

To a neat mixture of the alkenyl iodide 9 (1.5 eq) and the aldehyde 4(1.0 eq.) at room temperature was added 2.5 eq. of chromium chloridedoped with 0.5% NiCl₂ (w/w). The mixture was vortexed for about 2 min.to provide a homogeneous, green/grey paste and then stirred undernitrogen for an additional 10 min. after which time anhydrous DMF wasadded to bring the final reaction concentration to 0.36 M. The reactionmixture was deep green in color and was permitted to continue stirringat room temperature for 14 h. Following the allotted time, the reactionmixture was diluted with 1:1 EtOAc-hexanes and an aqueous 0.5 M EDTAsolution (pH 9) was added and the entire mixture was allowed to stir for1.5 h. The aqueous layer was extracted with three portions of EtOAc,dried (MgSO₄), filtered, and the filtrate was concentrated under reducedpressure to provide a green oil. The crude material was subjected tocolumn chromatography on SiO₂ (40% EtOAc-hexanes; elution was observedat 285 nm and 228 nm) to afford the product allylic alcohol 10 as a paleyellow oil that existed as a 1:1 mixture of diastereomers (47%): ¹H NMR(CD₂Cl₂) δ 0.94-1.00 (m, 6H), 1.13-1.16 (m, 9H), 1.54-1.57 (m, 9H),1.67-1.74 (m, 2H), 1.79-1.86 (m, 0.5H), 1.87-1.94 (m, 1H), 1.96-2.05 (m,0.5H), 2.09-2.24 (m, 2H), 2.66-2.77 (m, 1H), 2.85-2.99 (m, 1H),3.16-3.22 (m, 0.5H), 3.36-3.44 (m, 0.5H), 3.80-3.92 (m, 8H), 4.01-4.08(m, 0.5H), 4.12-4.17 (m, 0.5H), 4.30-4.38 (m, 0.5H), 4.66-4.77 (m,0.5H), 4.86-4.96 (m, 1H), 5.23-5.30 (m, 0.5H), 5.34-5.39 (m, 1H),5.39-5.43 (m, 0.5H), 6.68-6.72 (m, 1H), 6.73-6.77 (m, 0.5H), 6.77-6.81(m, 0.5H), 7.43-7.52 (m, 6H), 7.75-7.82 (m, 4H); ¹³C NMR (CD₂Cl₂) δ19.12, 26.83, 27.33, 27.45, 27.54, 27.59, 28.29, 28.41, 33.46, 33.48,38.30, 39.45, 43.64, 43.82, 44.93, 45.05, 45.48, 45.95, 50.95, 52.25,55.89, 55.99, 56.01, 61.14, 69.99, 73.06, 80.03, 80.49, 110.21, 110.56,111.87, 112.00, 112.02, 112.39, 125.92, 126.32, 126.35, 127.77, 129.57,129.69, 130.17, 134.15, 135.68, 147.85, 147.88, 147.99, 148.11, 148.71,149.59, 149.61, 155.79, 156.39.

Method 7 Oxidation of Allylic Alcohol 6 to Provide First Intermediate 12

To a 0.1 M solution of allylic alcohol 6 (1.0 eq) in dichloromethane at0° C. was added 1.1 eq. of the Dess-Martin reagent 11. The reactionmixture was allowed to stir, slowly warming to room temperature over 2.5h. The reaction was quenched by the addition of saturated aqueous sodiumbicarbonate solution and diluted with ethyl acetate. The organic andaqueous layers were partitioned and separated and the aqueous layerextracted with three additional portions of ethyl acetate. The combinedorganic extracts were washed with brine, dried (MgSO₄), filtered, andconcentrated under reduced pressure. The crude material was purified bycolumn chromatography on SiO₂ (10-30% EtOAc-hexanes, elution wasobserved at 285 nm and 228 nm). The product first intermediate 12 was acolorless, foul-smelling oil that existed at 26° C. as a 60:40 mixtureof rotamers in solution (66%): ¹H NMR (CDCl₃) δ 0.82 (apparent t, J=7.6Hz, 6H), 1.42 (s, 9H), 1.70 (apparent sept, J=6.62 Hz, 1H), 2.08-2.15(m, 1H), 2.15-2.24 (m, 1H), 2.62-2.70 (m, 1H), 2.75-2.91 (m, 1H),2.93-3.07 (m, 1H), 3.07-3.29 (m, 1.6H), 3.30-3.43 (m, 0.4H), 3.79 (s,3H), 3.81 (s, 3.4H), 4.04-4.16 (m, 0.6H), 5.52-5.62 (m, 1H), 5.69 (s,1H), 5.90 (s, 0.6H), 6.04 (s, 0.4H), 6.57 (s, 1H), 6.63 (s, 1H); ¹³C NMR(CDCl₃) δ 22.45, 27.04, 27.25, 28.11, 28.41, 38.01, 39.33, 40.39, 45.20,45.90, 51.62, 55.92, 55.98, 79.75, 80.23, 109.85, 110.25, 110.28,111.41, 125.65, 125.72, 126.26, 129.25, 147.57, 147.87, 148.16, 148.29,148.35, 154.40, 154.51, 199.53; HRMS-(ESI+) calcd for (C₂₄H₃₅NO₅)+H)[M+H]⁺ 418.2594, found 418.2590.

Method 8 Oxidation of Allylic Alcohol 8 to Provide First Intermediate 13

To a 0.1 M solution of 8 (1.0 eq) in dichloromethane at 0° C. was added1.1 eq. of the Dess-Martin reagent 11. The reaction mixture was allowedto stir, slowly warming to room temperature over 2.5 h. The reaction wasquenched by the addition of saturated aqueous sodium bicarbonatesolution and diluted with dichloromethane. The organic and aqueouslayers were partitioned and separated and the aqueous layer extractedwith three additional portions of dichloromethane. The combined organicextracts were washed with brine, dried (MgSO₄), filtered, andconcentrated under reduced pressure. The crude material was purified bycolumn chromatography on SiO₂ (10-50% EtOAc-hexanes, elution wasobserved at 285 nm and 228 nm). The product first intermediate 13 was acolorless, oil that existed at 26° C. as a 50:50 mixture of rotamers insolution (82%): ¹H NMR (CD₂Cl₂) δ 1.19 (s, 9H), 1.55 (s, 9H), 1.63-1.83(m, 5H), 2.34-2.57 (m, 2H), 2.70-2.85 (m, 1H), 2.85-3.05 (m, 1H),3.05-3.41 (m, 2.5H), 3.41-3.56 (m, 0.5H), 3.81-3.83 (m, 1H), 3.84 (s,3H), 3.86 (s, 3H), 3.97-4.08 (m, 0.5H), 4.20-4.35 (m, 0.5H), 5.68(apparent t, J=6.6 Hz, 1H), 5.87 (s, 1H), 6.09 (s, 0.5H), 6.19 (s,0.5H), 6.71 (s, 1H), 6.76 (s, 1H), 7.45-7.60 (m, 6H), 7.77-7.95 (m, 4H);¹³C NMR (CD₂Cl₂) δ 19.19, 24.66, 24.75, 26.83, 28.06, 28.28, 30.57,32.43, 37.75, 39.20, 45.16, 45.66, 63.84, 79.46, 79.77, 110.21, 110.49,111.81, 124.37, 124.67, 126.45, 127.76, 129.19, 129.68, 134.13, 135.61,147.79, 148.19, 149.20, 154.09, 154.41, 199.15, 199.27; HRMS-(ESI+)calcd for (C₄₀H₅₃NO₆Si+H) [M+H]⁺ 672.3720, found 672.3715.

Method 9 Oxidation of Allylic Alcohol 10 to Provide First Intermediate14

To a 0.1 M solution of allylic alcohol 10 (1.0 eq) in dichloromethane at0° C. was added 1.1 eq. of the Dess-Martin reagent 11. The reactionmixture was allowed to stir, slowly warming to room temperature over 5h. The reaction was quenched by the addition of saturated aqueous sodiumbicarbonate solution and diluted with dichloromethane. The organic andaqueous layers were partitioned and separated and the aqueous layerextracted with three additional portions of dichloromethane. Thecombined organic extracts were washed with brine, dried (MgSO₄),filtered, and concentrated under reduced pressure. The crude materialwas purified by column chromatography on SiO₂ (10-50% EtOAc-hexanes,elution was observed at 285 nm and 228 nm). The product firstintermediate 14 was a yellow foam that existed at 26° C. as a 50:50mixture of rotamers in solution (93%): ¹H NMR (CD₂Cl₂) δ 0.85 (s, 6H),1.14 (s, 9H), 1.48-1.57 (m, 9H), 1.65 (t, J=7.3 Hz, 2H), 2.30-2.50 (m,2H), 2.70-2.80 (m, 1H), 2.85-2.98 (m, 1H), 3.07-3.17 (m, 1H), 3.22-3.37(m, 1.5H), 3.38-3.50 (m, 0.5H), 3.81 (s, 3H), 3.85 (s, 3H), 3.85-3.92(m, 2H), 3.94-4.02 (m, 0.5H), 4.18-4.25 (m, 0.5H), 5.65-5.72 (m, 1H),5.74 (s, 1H), 6.07 (s, 0.5H), 6.14 (s, 0.5H), 6.69 (s, 1H), 6.76 (s,1H), 7.45-7.54 (m, 6H), 7.77-7.82 (m, 4H); ¹³C NMR (CD₂Cl₂) δ 19.09,26.80, 26.92, 26.97, 28.13, 28.22, 28.28, 33.22, 37.94, 39.39, 41.79,41.87, 44.49, 45.33, 46.02, 51.16, 51.44, 55.79, 55.83, 61.05, 79.47,79.76, 110.18, 110.51, 111.74, 126.40, 127.26, 127.36, 127.76, 129.48,129.69, 134.09, 135.66, 146.93, 147.06, 147.78, 148.10, 154.16, 154.47,199.36; HRMS-(ESI+) calcd for (C₄₂H₅₇NO₆Si—C₅H₉O₂(Boc)+H) [M-Boc+H]⁺600.3509, found 600.3496.

Method 10 Removal the Boc Protecting Group from First Intermediate 12and Amino Cyclization Provide (+)-Tetrabenazine 15

First intermediate 12 (1.0 eq) was dissolved in 10% Me₂S-dichloromethaneto provide an 82 mM solution. The solution was cooled to 0° C. andtriisopropylsilane (1.1 eq.) followed by TFA (precooled to 0° C.) wasadded to the reaction mixture to provide a final concentration of 41 mM.The reaction mixture was permitted to stir at 0° C. for 1 h. Followingthe allotted time the reaction mixture was quenched at 0° C. by theaddition of saturated aqueous potassium carbonate solution andconcentrated under reduced pressure to remove the majority of thedimethylsulfide. The mixture was extracted with five portions ofdichloromethane, and the combined organic extracts were washed withbrine, dried (MgSO₄), filtered and concentrated under reduced pressureto provide the crude product as a yellow solid. The crude product wasrecrystallized from 3.5% dimethoxyethane in hexanes. The resultingcolorless crystals were washed with hexanes to provide pure(+)-tetrabenazine (15) 46%: mp 126.0° C. (3.5% DME-hexanes) (a crystalpolymorph was observed at 116° C.); [α]²⁶ _(D)+37.2 (c 0.41, CH₂Cl₂); ¹HNMR (CD₂Cl₂) δ 0.89 (apparent t, J=7.2 Hz, 6H), 0.98 (ddd, J=12, 6.0,4.0 Hz, 1H), 1.59-1.68 (m, 1H), 1.74 (ddd, J=12, 5.9, 5.7 Hz, 1H), 2.32(apparent t, J=11.7 Hz, 1H), 2.46 (apparent t, J=12.3 Hz, 1H), 2.55(ddd, J=12, 10.0, 3.8 Hz, 1H), 2.65-2.73 (m, 2H), 2.83 (dd, J=5.5, 2.8Hz, 1H), 2.97-3.07 (m, 1H), 3.07-3.14 (m, 1H), 3.25 (dd, J=9.7, 6.3 Hz,1H), 3.47 (apparent d, J=12 Hz, 1H), 3.75 (s, 3H), 3.77 (s, 3H), 6.55(s, 1H), 6.60 (s, 1H) ¹³C NMR (CD₂Cl₂) δ 21.98, 23.02, 25.51, 29.46,35.16, 47.47, 47.63, 50.47, 55.87, 56.01, 61.47, 62.46, 108.46, 111.72,126.37, 128.96, 147.65, 147.98, 209.72; HRMS-(ESI+) calcd for(C₁₉H₂₇NO₃+H) [M+H]⁺ 318.2069, found 318.2082.

Method 11 Removal the Boc Protecting Group from First Intermediate 13and Amino Cyclization Provide (+)-TBZ Compound 16

The first intermediate starting material 13 (1.0 eq) was dissolved in10% Me₂S-dichloromethane to provide an 26 mM solution. The solution wascooled to 0° C. and triisopropylsilane (1.1 eq.) followed by TFA(precooled to 0° C.) was added to the reaction mixture to provide afinal concentration of 13 mM. The reaction mixture was permitted to stirat 0° C. for 1 h. Following the allotted time the reaction mixture wasquenched at 0° C. by the addition of saturated aqueous potassiumcarbonate solution and concentrated under reduced pressure to remove themajority of the dimethylsulfide. The mixture was extracted with fiveportions of dichloromethane, and the combined organic extracts werewashed with brine, dried (MgSO₄), filtered and concentrated underreduced pressure to provide an orange oil. The isolated material wasimmediately subjected to purification by flash chromatography on SiO₂(20-30% EtOAc-hexanes, elution was observed at 285 nm and 228 nm). Thesemipure product (existed as a mixture of diastereomers heavily favoringthe desired product) was subjected to crystallization from 3.5%dimethoxyethane in hexanes over several days. The resulting colorlesscrystals were washed with hexanes to provide (+)-TBZ compound 16 as asingle diastereomer 42%: [α]²⁶ _(D)+40.1 (c 0.63, CH₂Cl₂); ¹H NMR(CD₂Cl₂) δ 1.14 (s, 9H), 1.18-1.30 (m, 1H), 1.45-1.56 (m, 2H), 1.60-1.75(m, 2H), 1.86-1.98 (m, 1H), 2.41 (apparent t, J=11.4 Hz, 1H), 2.47(apparent t, J=12.6 Hz, 1H), 2.59-2.82 (m, 3H), 2.93 (dd, J=13.1, 2.8Hz, 1H), 3.06-3.20 (m, 2H), 3.34 (dd, J=9.6, 6.1 Hz, 1H), 3.55 (apparentd, J=11.6 Hz, 1H), 3.78 (apparent t, J=6.3 Hz, 2H), 3.84 (s, 3H), 3.85(s, 3H), 6.64 (s, 1H), 6.69 (s, 1H), 7.40-7.53 (m, 6H), 7.70-7.81 (m,4H); ¹³C NMR (CD₂Cl₂) δ 19.14, 23.43, 25.98, 26.74, 29.47, 32.77, 47.55,49.42, 50.44, 55.74, 55.86, 61.06, 62.36, 63.81, 108.31, 111.68, 126.31,127.68, 128.91, 129.60, 134.15, 135.59, 147.59, 147.90, 209.36;HRMS-(ESI+) calcd for (C₃₅H₄₅NO₄Si+H) [M+H]⁺ 572.3196, found 572.3187.

Method 12 Removal the Boc Protecting Group from First Intermediate 14and Amino Cyclization Provide (+)-TBZ Compound 17

The starting material 14 (1.0 eq) was dissolved in 10%Me₂S-dichloromethane to provide a 176 mM solution of the startingmaterial. The solution was cooled to 0° C. and triisopropylsilane (1.1eq.) followed by TFA (precooled to 0° C.) was added to the reactionmixture to provide a final concentration of 88 mM. The reaction mixturewas permitted to stir at 0° C. for 1 h. Following the allotted time thereaction mixture was quenched at 0° C. by the addition of saturatedaqueous potassium carbonate solution and concentrated under reducedpressure to remove the majority of the dimethylsulfide. The mixture wasextracted with five portions of dichloromethane, and the combinedorganic extracts were washed with brine, dried (MgSO₄), filtered andconcentrated under reduced pressure to provide a yellow foam. The crudeproduct was purified by flash chromatography on SiO₂ (0.2%triethylamine-10% EtOAc-89.8% hexanes to 0.2% triethylamine-50%EtOAc-49.8% hexanes, elution was observed at 285 nm and 228 nm). Theproduct (+)-TBZ compound 17 was a colorless foam consisting of only thedesired diastereomer 73%: ¹H NMR (CD₂Cl₂) δ 0.79 (dd, J=13.8, 3.8 Hz,1H), 0.92 (s, 6H), 1.14 (s, 9H), 1.59-1.72 (m, 2H), 2.27 (dd, J=13.2,5.1 Hz, 1H), 2.52-2.65 (m, 2H), 2.68-2.82 (m, 2H), 2.94 (dd, J=13.0, 3.0Hz, 1H), 3.06-3.18 (m, 2H), 3.25 (dd, J=9.8, 6.3 Hz), 3.55 (dd, J=11.6,1.8 Hz, 1H), 3.83-3.88 (m, 8H), 6.65 (s, 1H), 6.69 (s, 1H), 7.44-7.53(m, 6H), 7.74-7.82 (m, 4H); ¹³C NMR (CD₂Cl₂) δ 19.09, 26.79, 27.10,29.48, 32.31, 36.90, 44.38, 46.02, 47.45, 50.15, 55.77, 55.91, 61.09,62.53, 63.50, 108.38, 111.75, 126.30, 127.74, 128.93, 129.67, 134.13,135.65, 147.66, 147.98, 208.73; HRMS-(ESI+) calcd for (C₃₇H₄₉NO₄Si+H)[M+H]⁺ 600.3509, found 600.3499.

Method 13 Reduction of (+)-Tetrabenazine 15 to a Diasteromeric Mixtureof Dihydrotetrabenazine Compounds 18 and 19

To a 0.11 M solution of (+)-TBZ (15) in ethanol at 0° C. was added NaBH₄(2.85 eq). The reaction mixture was allowed to stir for 60 min. at roomtemperature. The solvent was carefully removed under reduced pressure,and the residue was taken up in dichloromethane and washed with threeportions of saturated aqueous K₂CO₃. The aqueous washings were backextracted with two portions of dichloromethane. The combined organicextracts were dried (MgSO₄), filtered, and concentrated under reducedpressure to provide a colorless oil that crystallized on standing underhigh vacuum. Purification of the crude product was achieved bychromatography on SiO₂ (2.5-5% MeOH—CH₂Cl₂, elution was observed at 285nm) UV active fractions were reanalyzed by TLC. Two products, 18 and 19,were isolated from this procedure. The major product 18 was a colorlesssolid 74%: [α]²⁶ _(D)+48 (c 0.30, CH₂Cl₂) ¹H NMR (CD₂Cl₂) δ 0.93 (d,J=6.6 Hz, 3H), 0.95 (d, J=6.6 Hz, 3H), 1.04 (ddd, J=14.6, 8.7, 4.3 Hz,1H), 1.42 (dd, J=20.2, 11.4 Hz, 1H), 1.59 (ddd, J=13.7, 9.6, 3.3 Hz,1H), 1.64-1.78 (m, 2H), 1.96 (apparent t, J=11.4 Hz, 1H), 2.27 (br s,1H), 2.40-2.48 (m, 1H), 2.54 (ddd, J=12.3, 3.7, 2.3 Hz, 1H), 2.60-2.67(m, 1H), 2.95-3.09 (m, 3H), 3.11 (apparent d, J=11.1 Hz, 1H), 3.35 (ddd,J=10.4, 10.4, 4.5 Hz, 1H), 3.80-3.81 (m, 6H), 6.60 (s, 1H), 6.69 (s,1H); ¹³C NMR (CD₂Cl₂) δ 21.61, 24.02, 25.33, 29.30, 39.68, 40.81, 41.58,51.83, 55.74, 55.91, 60.02, 60.92, 74.32, 108.42, 111.73, 126.68,129.76, 147.35, 147.61; HRMS-(ESI+) calcd for (C₁₉H₂₉NO₃+H) [M+H]⁺320.2226, found 320.2242. The minor product 19 was a yellow oil 4%: ¹HNMR (CD₂Cl₂) δ 0.94 (d, J=6.6 Hz, 3H), 0.96 (d, J=6.6 Hz, 3H), 1.13-1.20(m, 1H), 1.24-1.34 (m, 2H), 1.60-1.77 (m, 2H), 1.89-2.00 (m, 1H)2.36-2.44 (m, 2H), 2.53 (ddd, J=10.5, 10.5, 3.8 Hz, 1H), 2.58-2.70 (m,2H), 2.91-2.98 (m, 1H), 2.98-3.09 (m, 1H), 3.48 (apparent d, J=11.6 Hz,1H), 3.80-3.82 (apparent s, 6H), 4.07 (apparent d, J=3.1 Hz, 1H), 6.60(s, 1H), 6.68 (s, 1H); ¹³C NMR (CD₂Cl₂) δ 22.74, 22.81, 24.87, 29.30,37.83, 38.87, 39.42, 52.44, 55.76, 55.96, 56.32, 56.43, 67.88, 108.45,111.78, 127.18, 130.38, 147.30, 147.54.

Method 14 Ketalization of TBZ Compound 16

To an 87 mM solution of the starting material 16, 1.0 eq) in ethyleneglycol was added methane sulfonic acid (1.76 eq). The reaction mixturewas heated to and maintained at 85° C. for 20 h in a sealed vessel.Following the allotted time, the reaction mixture was quenched be theaddition of 1 mL of saturated aqueous potassium carbonate solution andEtOAc was added. The reaction mixture was stirred for an additional hourat room temperature after which time the aqueous and organic layers werepartitioned and separated. The aqueous layer was extracted with threeportions of CH₂Cl₂ and the combined organic extracts were dried (MgSO₄),filtered, and concentrated under reduced pressure to provide a yellowoil. Purification of the crude material was undertaken by flashchromatography on SiO₂ (1% triethylamine-DCM to 1% triethyamine-9%methanol-90% DCM; elution was observed at 284 nm and 240 nm). Poolsbelieved to contain the desired product were collected to provide ketal20 as a colorless oil 73%: ¹H NMR (CD₂Cl₂) δ 1.03-1.15 (m, 1H),1.20-1.35 (m, 2H), 1.37-1.61 (m, 4H), 1.87-1.99 (m, 1H), 2.08-2.17 (br.s, 1H), 2.20-2.29 (m, 2H), 2.42-2.51 (m, 1H), 2.55-2.64 (m, 1H),2.92-3.03 (m, 3H), 3.27 (apparent d, J=11 Hz, 1H), 3.57 (apparent t,J=6.3 Hz, 2H), 3.758 (s, 3H), 3.764 (s, 3H), 3.92-4.00 (m, 2H),4.00-4.09 (m, 2H), 6.56 (s, 1H), 6.57 (s, 1H); ¹³C NMR (CD₂Cl₂) δ 23.74,25.30, 29.31, 33.25, 41.00, 43.90, 55.74, 56.07, 58.68, 59.82, 62.64,63.68, 65.17, 63.35, 108.50, 109.65, 111.78, 126.82, 129.81, 147.31,147.67; LRMS-(ESI+) calcd for (C₂₁H₃₁NO₅+H) [M+H]⁺ 378.23, found 378.25.

Method 15 Fluorination of Hydroxy Ketal 20

To a 100 mM solution of the starting hydroxy ketal 20 in dichloromethanewas added DAST reagent (2.2 eq.) at room temperature. The reactionmixture was permitted to stir for 16 h after which time the reactionmixture was quenched by the addition of saturated aqueous NaHCO₃. Theaqueous and organic layers were partitioned and separated, and theaqueous layer was extracted with three portions of dichloromethane. Thecombined organic extracts were dried (MgSO₄), filtered, and concentratedunder reduced pressure to provide a yellow oil that was purified byflash chromatography on SiO₂ (1% triethylamine-DCM to 1% triethyamine-5%methanol-94% DCM, 40CV; elution was observed at 284 nm and 240 nm). Thepurified product alpha-fluoroalkyl ketal 21 was obtained as a yellow oilin 60% yield. The isolated material was taken on to the next stepwithout additional characterization.

Method 16 Preparation of Alpha-Fluoroalkyl Tetrabenazine Compound 22 ViaProtected Tetrabenazine Compound Alpha-Fluororalkyl Ketal 21

To an 8 mM solution of the starting fluoroalkyl ketal 21 in 3:1THF-water was added 0.18 g of DOWEX strongly acidic cation exchangeresin. The reaction mixture was heated to and maintained at 65° C.overnight. The resin was washed with saturated aqueous potassiumcarbonate and the mixture was extracted with three portions ofdichloromethane and three portions of toluene. The organic extracts werecombined, dried (MgSO₄), filtered, and concentrated under reducedpressure. The crude material was purified by semi-preparative HPLC on aPhenomenex Gemini C₁₈ column 5 μm, (4.6×250 mm; UV @ 284 nm and 240 nm)at a Flow rate of 1.0 mL/min. The following gradient was used: 100% 0.1mM TEAA buffer pH 7.0 and holding for 3 min. then ramping to 98% MeCN 2%0.1 mM TEAA buffer pH 7.0 over 25 min and finally holding at this levelfor an additional 12 min. The column was maintained at room temperatureduring the analysis. The major UV active peak eluted at 34.8 min and wascollected and concentrated under reduced pressure to provide the productas a yellow oil 5%: LRMS-(ESI+) calcd for (C₁₉H₂₆FNO₃+H) [M+H]⁺ 336.20,found 336.16.

Method 17 Preparation of Dihydrotetrabenazine Compound 23

To a 0.1 M solution of tetrabenazine compound 16 in ethanol at 0° C. wasadded NaBH₄ (2.85 eq). The reaction mixture was allowed to stir for 60min. at room temperature. The excess solvent was carefully removed underreduced pressure, and the residue was taken up in dichloromethane andwashed with three portions of saturated aqueous K₂CO₃. The aqueouswashings were back extracted with two portions of dichloromethane. Thecombined organic extracts were dried (MgSO₄), filtered, and concentratedunder reduced pressure to provide a yellow foam. Purification of thecrude product was achieved by chromatography on SiO₂ (2.5-5%MeOH—CH₂Cl₂, elution was observed at 285 nm). The productdihydrotetrabenazine compound 23 was a colorless foam 78%: ¹H NMR(CD₂Cl₂) δ 1.09-1.22 (m, 11H), 1.44 (dd, J=20.1, 11.6 Hz, 2H), 1.55-1.72(m, 4H), 1.78-1.88 (m, 1H), 2.02 (apparent t, J=11.4 Hz, 1H), 2.46 (ddd,J=4.6, 11.3, 10.3 Hz, 1H), 2.57 (ddd, J=13.1, 3.8, 2.5 Hz, 1H), 2.65(dd, J=14.3, 4.0 Hz, 1H), 2.94-3.10 (m, 3H), 3.14 (apparent d, J=11.1Hz, 1H), 3.40 (ddd, J=9.5, 9.5, 4.6 Hz, 1H), 3.76 (apparent t, J=6.3 Hz,2H), 3.83 (apparent s, 6H), 6.63 (s, 1H), 6.73 (s, 1H), 7.42-7.49 (m,6H), 7.71-7.76 (m, 4H), ¹³C NMR (CD₂Cl₂) δ 19.17, 23.21, 26.75, 29.38,29.79, 33.03, 40.89, 43.88, 51.86, 55.76, 55.94, 59.78, 60.95, 63.93,73.92, 108.48, 111.76, 126.75, 127.69, 129.61, 129.81, 134.23, 135.62,147.38, 147.63; HRMS-(ESI+) calcd for (C₃₅H₄₇NO₄Si+H) [M+H]⁺ 574.3353,found 574.3333.

Method 18 Preparation of Dihydrotetrabenazine Compound 24 and 2-epi-24

To a 0.1 M solution of tetrabenazine compound 17 in ethanol at 0° C. wasadded NaBH₄ (2.85 eq). The reaction mixture was allowed to stir for 60min. at room temperature. The excess solvent was carefully removed underreduced pressure, and the residue was taken up in dichloromethane andwashed with three portions of saturated aqueous K₂CO₃. The aqueouswashings were back extracted with two portions of dichloromethane. Thecombined organic extracts were dried (MgSO₄), filtered, and concentratedunder reduced pressure to provide a yellow foam. Purification of thecrude product dihydrotetrabenazine compound 24 was achieved bychromatography on SiO₂ (2.5-5% MeOH—CH₂Cl₂, elution was observed at 285nm). The product 24 was a colorless foam 69%: ¹H NMR (CD₂Cl₂) δ 0.99 (s,6H), 1.02-1.06 (m, 1H), 1.16 (s, 9H), 1.48 (dd, J=20.2, 11.4 Hz, 1H),1.63-1.82 (m, 4H), 2.06 (apparent t, J=11.4 Hz, 1H), 2.47 ((ddd, J=3.8,10.6, 10.6 Hz, 1H), 2.60 (ddd, J=12.0, 3.4, 2.3 Hz, 1H), 2.68 (apparentbr d, J=15.4 Hz, 1H), 2.96-3.04 (m, 1H), 3.05-3.14 (m, 2H), 3.17(apparent br d, J=11.4 Hz, 1H), 3.31 (ddd, J=9.3, 9.3, 4.3 Hz, 1H), 3.85(s, 6H), 3.87-3.92 (m, 2H), 6.66 (s, 1H), 6.75 (s, 1H), 7.43-7.56 (m,6H), 7.76-7.86 (m, 4H); ¹³C NMR (CD₂Cl₂) δ 19.10, 26.83, 27.67, 27.77,29.28, 32.73, 39.98, 40.64, 42.21, 44.66, 49.89, 51.75, 55.77, 55.94,61.02, 61.24, 62.71, 73.88, 108.46, 111.79, 126.62, 127.76, 129.70,134.10, 135.68, 147.44, 147.69. A small amount of the ring position-2epimer of dihydrotetrabenazine compound 24 was isolated in about 12%yield and was characterized. The epimeric product, 2-epi-24, was a paleyellow oil: ¹H NMR (CD₂Cl₂) δ 0.92 (s, 6H), 0.96-1.02 (m, 2H), 1.08 (s,9H), 1.42 (dd, J=14.5, 4.7 Hz, 1H), 1.61-1.71 (m, 3H), 1.86-1.95 (m,1H), 2.35 (apparent dt, J=13.7, 2.9 Hz, 1H), 2.43 (apparent t, J=11.6Hz, 1H), 2.51 (ddd, J=11.4, 11.4, 3.9 Hz, 1H), 2.59-2.67 (m, 2H),2.88-2.95 (m, 1H), 2.98-3.11 (m, 1H), 3.45 (br d, J=11.4 Hz, 1H),3.76-3.88 (m, 8H), 3.94-4.01 (m, 1H), 6.61 (s, 1H), 6.67 (s, 1H),7.40-7.54 (m, 6H), 7.68-7.81 (m, 4H); ¹³C NMR (CD₂Cl₂) δ 19.05, 26.72,27.51, 29.31, 29.78, 32.81, 36.51, 39.36, 41.99, 44.53, 52.34, 55.77,55.86, 55.96, 57.71, 61.16, 69.62, 108.45, 111.80, 127.19, 127.71,129.64, 130.43, 134.12, 135.65, 147.30, 147.53. The minor epimer,2-epi-24, was converted by a series of steps analogous to Method steps19 (protection of the hydroxy methine group as a THP ether to provide2-epi-26), 21 (removal of the t-butyldiphenylsilyl group to provide2-epi-28), and 23 (reaction of the primary hydroxy group with DAST toprovide 2-epi-30); and then removal of the THP ether protecting group ina step analogous to that described in Example 3 to provide thealpha-fluoroalkyl dihydrotetrabenazine 2-epi-32 (See Table 15), acompound identical in structure to compound 32 in all respects save theconfiguration at ring position-2 which is “S” rather than “R”. Theintermediate 2-epi-28 was characterized by low resolution massspectroscopy: LRMS-(ESI+) calcd for (C₂₄H₃₇NO₅+H) [M+H]⁺ 448.31, found448.26. Alpha-fluoroalkyl dihydrotetrabenazine 2-epi-32 wascharacterized by high resolution mass spectroscopy: HRMS-(ESI+) calcdfor (C₂₁H₃₂FNO₃+H) [M+H]⁺ 366.24445, found 366.24333.

Method 19 Preparation of THP Protected DTBZ Compound 25

To a 0.1M solution of the starting dihydrotetrabenazine compound 23 (1.0eq) in dichloromethane was added methane sulfonic acid (1.1 eq),followed by dihydropyran (2.2 eq.). The reaction was permitted to stirat 26° C. for 36 h. Following this time, the reaction mixture wasquenched by the addition of saturated aqueous potassium carbonatesolution. Dichloromethane was added, and the aqueous and organic layerswere partitioned and separated. The aqueous layer was extracted withthree portions of CH₂Cl₂, and the combined organic extracts were dried,(MgSO₄), filtered, and concentrated under reduced pressure to provide ayellow oil that was immediately subjected to purification by flashchromatography on SiO₂ (1% triethylamine-DCM to 1% triethyamine-5%methanol-94% DCM; elution was observed at 284 nm and 240 nm). Fractionspresumed to contain the desired product were concentrated under reducedpressure to provide protected dihydrotetrabenazine compound 25 as a paleyellow oil that existed as a roughly 1:1 mixture of diastereomers 75%:¹H NMR (CD₂Cl₂) δ 1.10 (s, 9H), 1.48-1.65 (m, 8H), 1.66-1.79 (m, 4H),1.80-1.90 (m, 1.5H), 1.91-1.99 (m, 0.5H), 1.99-2.11 (m, 1H), 2.40-2.51(m, 1H), 2.62-2.68 (m, 1H), 2.68-2.76 (m, 1H), 2.95-3.16 (m, 3H),3.29-3.37 (m, 0.5H), 3.49-3.58 (m, 1.5H), 3.71-2.78 (dd, J=9.4, 6.1 Hz,2H); 3.79-3.86 (m, 6H), 3.86-3.94 (m, 1H), 3.95-4.07 (m, 1H), 4.65-4.71(m, 0.5H), 4.92-5.01 (m, 0.5H), 6.60-6.64 (s, 1H), 6.69-6.72 (s, 0.5H),6.72-6.75 (s, 0.5H), 7.39-7.50 (m, 6H), 7.68-7.77 (m, 4H); ¹³C NMR(CD₂Cl₂) δ 19.16, 19.69, 20.24, 23.17, 23.23, 25.65, 25.67, 25.72,26.74, 29.43, 29.46, 29.78, 29.90, 30.69, 31.14, 31.21, 33.06, 33.11,36.00, 39.52, 41.61, 42.49, 51.77, 51.95, 55.76, 56.04, 56.17, 59.91,59.99, 60.72, 61.00, 62.31, 62.50, 62.87, 63.96, 64.10, 75.58, 82.46,94.06, 101.79, 108.75, 108.80, 111.76, 111.82, 126.83, 126.98, 127.68,129.58, 130.00, 130.04, 134.23, 134.25, 134.26, 134.28, 135.61, 147.35,147.38, 147.68, 147.71

Method 20 Preparation of THP Protected DTBZ Compound 26

To a 0.1M solution of the starting dihydrotetrabenazine compound 24 (1.0eq) in dichloromethane was added methane sulfonic acid (1.1 eq),followed by dihydropyran (2.2 eq.). The reaction was permitted to stirat 26° C. for 36 h. Following this time, the reaction mixture wasquenched be the addition of saturated aqueous potassium carbonatesolution. Dichloromethane was added, and the aqueous and organic layerswere partitioned and separated. The aqueous layer was extracted withthree portions of CH₂Cl₂, and the combined organic extracts were dried,(MgSO₄), filtered, and concentrated under reduced pressure to provideprotected dihydrotetrabenazine compound 26 as a yellow foam that existedas a roughly 1:1 mixture of diastereomers the crude product was taken onto the next step without additional purification 99%.

Method 21 Preparation of Alpha-Hydroxyalkyl ProtectedDihydrotetrabenazine Compound 27

To a 0.3 M solution of the protected dihydrotetrabenazine compound 25 inTHF was added a 1.0 M tetrabutylammonium fluoride (TBAF) solution in THF(3.3 eq) bringing the final reaction concentration to 0.15 M withrespect to the starting material 25. The reaction mixture was allowed tocontinue stirring at room temperature for 14 h. The mixture was dilutedwith deionized water, and extracted with three portions ofdichloromethane. The combined organic extracts were dried (MgSO₄),filtered, and concentrated under reduced pressure to provide a yellowoil. The crude material was purified by column chromatography on SiO₂(1% triethylamine-DCM to 1% triethyamine-10% methanol-89% DCM; elutionwas observed at 284 nm and 240 nm). The product alpha-hydroxyalkylprotected dihydrotetrabenazine compound 27 eluted late in the run as abroad peak. The product was a 1:1 mixture of diastereomers thatpresented as a pale yellow oil 60%: ¹H NMR (CD₂Cl₂) δ 1.11-1.33 (m,2.0H), 1.48-1.66 (m, 8.0 H), 1.69-1.80 (m, 2.5 H), 1.81-1.95 (1.5 H),1.98-2.13 (m, 1.0 H), 2.21-2.38 (m, 1.0 H), 2.40-2.52 (m, 1.0 H),2.58-2.67 (m, 1.5 H), 2.70 (ddd, J=12.5, 3.8, 2.5 Hz, 0.5H), 2.95-3.15(m, 4.0 H), 3.33 (ddd, J=9.5, 9.5, 4.5 Hz, 0.5 H), 3.51-3.59 (m, 1.5 H),3.62 (apparent dd, J=9.7, 6.3 Hz, 2.0 H), 3.81 (apparent s, 4.5 H), 3.82(s, 1.5 H), 3.82-3.96 (m, 0.5 H), 3.97-4.04 (m, 0.5 H), 4.69 (dd, J=3.6,2.8 Hz, 0.5 H), 4.89-4.94 (m, 0.5 H), 6.60 (apparent d, J=1.8 Hz, 1.0H), 6.70 (apparent d, J=3.5 Hz, 1.0 H); ¹³C NMR (CD₂Cl₂) δ 19.99, 20.19,22.91, 23.16, 25.64, 25.66, 29.28, 29.32, 29.71, 29.78, 31.13, 31.32,33.13, 33.24, 35.96, 39.35, 41.38, 42.32, 51.66, 51.85, 55.74, 56.01,56.16, 59.82, 59.93, 60.68, 60.95, 62.32, 62.55, 62.83, 62.86, 75.96,82.35, 94.72, 101.75, 108.71, 108.74, 111.71, 111.78, 126.71, 126.89,129.78, 129.82, 147.34, 147.37, 147.69, 147.73; LRMS-(ESI+) calcd for(C₂₄H₃₇NO₅+H) [M+H]⁺ 448.31, found 448.25.

Method 22 Preparation of Alpha-Hydroxyalkyl ProtectedDihydrotetrabenazine Compound 28

To a 0.3 M solution of the doubly protected dihydrotetrabenazinecompound 26 in THF was added a 1.0 M TBAF solution in THF (3.3 eq)bringing the final reaction concentration to 0.15 M with respect to thestarting material 26. The reaction mixture was allowed to continuestirring at room temperature for 14 h. The mixture was diluted withdeionized water, and extracted with three portions of dichloromethane.The combined organic extracts were dried (MgSO₄), filtered, andconcentrated under reduced pressure to provide a yellow oil. The crudematerial was purified by column chromatography on SiO₂ (1%triethylamine-DCM to 1% triethyamine-10% methanol-89% DCM; elution wasobserved at 284 nm and 240 nm). The product eluted late in the run as abroad peak. The product alpha-hydroxyalkyl protecteddihydrotetrabenazine compound 28 was a 1:1 mixture of diastereomers thatpresented as a colorless oil 71%: ¹H NMR (CD₂Cl₂) δ 0.90-1.10 (m, 6.5H),1.23-1.39 (m, 0.5H), 1.48-1.69 (m, 7.0H), 1.71-1.94 (m, 4.0H), 2.08 (m,1.0H), 2.38-2.83 (m, 4.0H), 2.93-3.16 (m, 3.5H), 3.22 (ddd, J=9.5, 9.5,4.5 Hz, 0.5H), 3.40-3.60 (m, 1.5H), 3.61-3.76 (m, 2.0H), 3.77-3.91 (m,6H), 3.92-4.06 (m, 1.5H), 4.62-4.83 (m, 0.5H), 4.83-5.09 (m, 0.5H), 6.60(apparent d, J=1.8 Hz, 1.0 H), 6.70 (apparent d, J=3.5 Hz, 1.0 H); ¹³CNMR (CD₂Cl₂) δ 19.96, 25.67, 27.62, 27.71, 27.89, 29.26, 29.30, 31.18,31.28, 32.78, 35.87, 37.52, 38.28, 39.34, 41.47, 41.95, 45.18, 45.29,51.50, 51.74, 55.72, 55.99, 56.15, 59.12, 59.19, 60.60, 60.85, 62.58,62.71, 62.82, 62.94, 76.16, 83.14, 94.56, 102.07, 108.75, 111.73,111.81, 126.69, 126.86, 129.86, 129.93, 147.33, 147.37, 147.67, 147.73;LRMS-(ESI+) calcd for (C₂₆H₄₁NO₅+H) [M+H]⁺ 448.31, found 448.25.

Example 1 Preparation of Alpha-Fluoroalkyl ProtectedDihydrotetrabenazine Compound 29

To a 60 mM solution of the starting alpha-hydroxyalkyl protecteddihydrotetrabenazine compound 27 in dichloromethane was addeddiethylaminosulfur trifluoride (DAST, 2.2 eq.) at room temperature. Thereaction was stirred for 14 h at this temperature, and then quenched bythe addition of saturated aqueous potassium carbonate solution. Theaqueous and organic layers were partitioned, and the aqueous layer wasextracted with two portions of dichloromethane. The combined organicextracts were dried (MgSO₄), filtered, and concentrated under reducedpressure to provide an orange oil that was purified by flashchromatography on SiO₂ (1% triethylamine-DCM to 1% triethyamine-10%methanol-89% DCM, 40CV; elution was observed at 284 nm and 240 nm). Thedesired product eluted as a broad peak, late in the run. The productalpha-fluoroalkyl protected dihydrotetrabenazine compound 29 was a paleyellow oil that existed as a 1:1 mixture of diastereomers 58%: ¹H NMR(CD₂Cl₂) δ 1.12-1.31 (m, 2.0H), 1.50-1.67 (m, 6.0H), 1.66-1.91 (m,6.0H), 1.99-2.12 (m, 1.0H), 2.39-2.51 (m, 1.0H), 2.59-2.67 m, 1.5H),2.71 (ddd, J=12.5, 3.8, 2.5 Hz, 0.5H), 2.93-3.15 (m, 4.0H), 3.33 (ddd,J=9.3, 9.3, 4.5 Hz, 0.5H), 3.49-3.59 (m, 1.5H), 3.76-3.87 (m, 6.0H),3.88-3.94 (m, 0.5H), 3.97-4.04 (m, 0.5H), 4.42 (ddd, J=6.1, 4.3, 6.1 Hz,1.0H), 4.54 (ddd, J=6.1, 4.3, 6.1 Hz, 1.0H), 4.66-4.74 (m, 0.5H),4.91-4.99 (m, 0.5H), 6.56-6.66 (m, 1.0H), 6.68-6.78 (m, 1.0H); ¹³C NMR(CD₂Cl₂) δ 19.79, 20.22, 22.60, 22.63, 22.66, 22.69, 25.66, 25.72,29.42, 29.46, 29.65, 29.76, 30.73, 30.79, 30.92, 30.98, 31.15, 31.25,36.02, 39.50, 41.57, 42.41, 51.75, 51.93, 55.76, 56.04, 56.17, 59.88,59.96, 60.70, 60.97, 62.49, 62.89, 75.83, 82.45, 83.39, 83.49, 85.01,85.12, 94.29, 101.76, 108.75, 108.79, 111.75, 111.82, 126.83, 126.99,129.96, 130.01, 147.35, 147.38, 147.67, 147.72; LRMS-(ESI+) calcd for(C₂₄H₃₆FNO₄+H) [M+H]⁺ 422.27, found 422.23.

Example 2 Preparation of Alpha-Fluoroalkyl ProtectedDihydrotetrabenazine Compound 30

To a 60 mM solution of the starting alpha-hydroxyalkyl protecteddihydrotetrabenazine compound 28 in dichloromethane was addeddiethylaminosulfur trifluoride (DAST, 2.2 eq.) at room temperature. Thereaction was stirred for 14 h at this temperature, and then quenched bythe addition of saturated aqueous potassium carbonate solution. Theaqueous and organic layers were partitioned, and the aqueous layer wasextracted with two portions of dichloromethane. The combined organicextracts were dried (MgSO₄), filtered, and concentrated under reducedpressure to provide an orange oil that was purified by flashchromatography on SiO₂ (1% triethylamine-DCM to 1% triethyamine-10%methanol-89% DCM, 40CV; elution was observed at 284 nm and 240 nm). Thedesired product eluted as a broad peak, late in the run. The productalpha-fluoroalkyl protected dihydrotetrabenazine compound 30 was an oilthat existed as a 1:1 mixture of diastereomers 46%. The isolatedmaterial was taken on to the next step without additionalcharacterization or analysis.

Method 23 Preparation of Alpha-Fluoroalkyl Dihydrotetrabenazine Compound31

The starting material, alpha-fluoroalkyl protected dihydrotetrabenazinecompound 29, was dissolved in 0.1 M HCl in MeOH to provide a 26 mMsolution of the starting material 29. The reaction mixture was permittedto stir for 1.5 h at room temperature. The solvent was removed underreduced pressure, and the residue was dried under high vacuum for onehour. The residue was treated with aqueous potassium carbonate solutionand extracted with three portions of dichloromethane. Thedichloromethane extracts were dried, (MgSO₄) filtered, and concentratedunder reduced pressure to provide the desired product alpha-fluoroalkyldihydrotetrabenazine 31 as a colorless solid 99%: ¹H NMR (CD₂Cl₂) δ1.15-1.26 (m, 1H), 1.47 (m, 2H), 1.54-1.91 (m, 6H), 2.05 (apparent t,J=11.4 Hz, 1H), 2.43-2.51 (m, 1H), 2.56 (ddd, J=12.3, 3.8, 2.5 Hz, 1H),2.60-2.68 (m, 1H), 2.96-3.09 (m, 3H), 3.15 (apparent d, J=11.1 Hz, 1H),3.42 (ddd, J=9.5, 9.5, 4.6 Hz, 1H), 3.81 (s, 6H), 4.42 (t, J=6.1 Hz,1H), 4.54 (t, J=6.1 Hz, 1H), 6.61 (s, 1H), 6.70 (s, 1H); ¹³C NMR(CD₂Cl₂) δ 22.80 (d_(C*-C—C—F), J=5.1 Hz), 29.41, 29.80, 30.99(d_(C*-C—F), J=19.0 Hz), 41.02, 43.91, 51.93, 55.90, 56.07, 59.79,61.05, 74.00, 84.36 (d_(C*-F), J=163.2 Hz), 108.58, 111.88, 126.79,129.68, 147.55, 147.82; LRMS-(ESI+) calcd for (C₁₉H₂₈FNO₃+H) [M+H]⁺338.21, found 338.20.

Method 24 Preparation of Alpha-Fluoroalkyl Dihydrotetrabenazine Compound32

The starting material was dissolved in 0.1 M HCl in MeOH to provide a 26mM solution of the starting material 30. The reaction mixture waspermitted to stir for 1.5 h at room temperature. The solvent was removedunder reduced pressure, and the residue was dried under high vacuum forone hour. The residue was treated with aqueous potassium carbonatesolution and extracted with three portions of dichloromethane. Thedichloromethane extracts were dried, (MgSO₄) filtered, and concentratedunder reduced pressure to provide the desired product alpha-fluoroalkyldihydrotetrabenazine 32 as colorless solid 99%: ¹H NMR (CD₂Cl₂) δ0.92-0.97 (m, 1H), 1.01 (s, 6H), 1.03-1.11 (m, 1H), 1.42 (q, J=11.4 Hz,1H), 1.62-1.85 (m, 1H), 2.06 (t, J=11.4 Hz, 1H), 2.39-2.49 (m, 1H), 2.57(ddd, J=12.3, 3.8, 2.5 Hz, 1H), 2.60-2.68 (m, 1H), 2.94-3.08 (m, 3H),3.14 (apparent d, J=11.1 Hz, 1H), 3.33 (ddd, J=9.5, 9.5, 4.6 Hz, 1H),3.81 (s, 6H), 4.54 (ddd, 6.2, 6.2, 2.0 Hz, 1H), 4.66 (ddd, 6.2, 6.2, 1.8Hz, 1H), 6.60 (s, 1H), 6.69 (s, 1H); ¹³C NMR (CD₂Cl₂) δ 27.47, 27.65,29.33, 32.65 (d_(C*-C—C—F), J=4.4 Hz), 40.09, 40.87, 42.07(d_(C*-C—F, J=)17.6 Hz), 42.09, 51.75, 55.78, 55.94, 60.94, 62.64,74.09, 82.16 (d_(C*-F), J=161.7 Hz), 108.40, 111.76, 126.69, 129.73,147.42, 147.66; HRMS-(ESI+) calcd for (C₂₁H₃₂FNO₃+H) [M+H]⁺ 366.24445,found 366.24404.

Method 25 Preparation of Fluorophilic Protected Tetrabenazine Tosylate33 Via Intermediate Protected Tetrabenazine Alcohol 20.

To a solution of alpha-hydroxyalkyl protected TBZ compound 20 inpyridine is added toluene sulfonyl chloride (tosyl chloride 1.5equivalents) and the mixture is stirred at 0° C. and periodicallymonitored by thin layer chromatography (tlc). When tlc indicatescomplete consumption of the starting alcohol 20, the reaction mixture isquenched by adding ice-cold water and EtOAc. The organic layer is washedsuccessively with water, 1M HCl (5×), saturated Na₂CO₃ and brine. Theorganic layer is dried over anhydrous Na₂SO₄, filtered and concentratedunder reduced pressure. The residue is chromatographed on silica gel toafford fluorophilic protected TBZ tosylate 33.

Method 26 Preparation of Fluorophilic Protected Tetrabenazine Tosylate34 Via Intermediate Protected Tetrabenazine Alcohol 27

To a solution of alpha-hydroxyalkyl protected TBZ compound 27 inpyridine is added toluene sulfonyl chloride (tosyl chloride 1.5equivalents) and the mixture is stirred at 0° C. and periodicallymonitored by thin layer chromatography (tlc). When tlc indicatescomplete consumption of the starting alcohol 20, the reaction mixture isquenched by adding ice-cold water and EtOAc. The organic layer is washedsuccessively with water, 1M HCl (5×), saturated Na₂CO₃ and brine. Theorganic layer is dried over anhydrous Na₂SO₄, filtered and concentratedunder reduced pressure. The residue is chromatographed on silica gel toafford fluorophilic protected TBZ tosylate 34.

Method 27 Preparation of PET Imaging Agent 35

To a Teflon-lined reaction vial contained in a shielded hood and fittedwith a nitrogen purge inlet and magnetic spin bar, is added about 1milliliter of an aqueous acetonitrile solution F-18 fluoride ion,potassium carbonate (about 1 mg), and Kryptofix 221 (about 10 mg). Thevial is heated at 100° C. under a stream of nitrogen to effect theazeotropic removal of water. Additional dry acetonitrile (1 mL) is addedand evaporated. This azeotropic drying protocol is repeated three times.After the final evaporation step a mixture of dimethyl formamide andacetonitrile (about 1 mL) containing fluorophilic protected TBZ tosylate33 (2 mg) is added and the vial is sealed. The reaction mixture isstirred and heated at 100° C. for 10 minutes and then is cooled to roomtemperature. The product mixture comprising the starting tosylate 33 andthe product F-18 alpha-fluoroalkyl protected tetrabenazine is dilutedwith water (10 mL) and applied to a Sep-Pak cartridge. The cartridge isthen washed with water (3×) to remove unreacted fluoride ion and otherwater soluble components of the product mixture. The radiolabledalpha-fluoroalkyl protected tetrabenazine compound and starting tosylate33 are then eluted from the cartridge with acetonitrile. Most of theacetonitrile is then evaporated and the residue is dissolved in aqueousmethanol containing hydrochloric acid (HCl) and heated at 60° C. Themixture is again concentrated and subjected to preparative reverse phaseHPLC to afford an aqueous formulation comprising PET imaging agent 35.

Method 28 Preparation of PET Imaging Agent 36

To a Teflon-lined reaction vial contained in a shielded hood and fittedwith a nitrogen purge inlet and magnetic spin bar, is added about 1milliliter of an aqueous acetonitrile solution F-18 fluoride ion,potassium carbonate (about 1 mg), and Kryptofix 221 (about 10 mg). Thevial is heated at 100° C. under a stream of nitrogen to effect theazeotropic removal of water. Additional dry acetonitrile (1 mL) is addedand evaporated. This azeotropic drying protocol is repeated three times.After the final evaporation step a mixture of dimethyl formamide andacetonitrile (about 1 mL) containing fluorophilic protected DTBZtosylate 34 (2 mg) is added and the vial is sealed. The reaction mixtureis stirred and heated at 100° C. for 10 minutes and then is cooled toroom temperature. The product mixture comprising the starting tosylate34 and the intermediate F-18 alpha-fluoroalkyl protecteddihydrotetrabenazine is diluted with water (10 mL) and applied to aSep-Pak cartridge. The cartridge is then washed with water (3×) toremove unreacted fluoride ion and other water soluble components of theproduct mixture. The radiolabled alpha-fluoroalkyl intermediate andstarting tosylate 34 are then eluted from the cartridge withacetonitrile. Most of the acetonitrile is then evaporated and theresidue is dissolved in aqueous acetonitrile and treated with DOWEXstrongly acidic cation exchange resin at 65° C. for 10 minutes. Thereaction mixture is then filtered and subjected to preparative reversephase HPLC to afford an aqueous formulation comprising PET imaging agent36.

Method 29 Alternate Preparation of PET Imaging Agent 36

To a Teflon-lined reaction vial contained in a shielded hood and fittedwith a nitrogen purge inlet and magnetic spin bar, is added about 1milliliter of an aqueous acetonitrile solution F-18 fluoride ion,potassium carbonate (about 1 mg), and Kryptofix 221 (about 10 mg). Thevial is heated at 100° C. under a stream of nitrogen to effect theazeotropic removal of water. Additional dry acetonitrile (1 mL) is addedand evaporated. This azeotropic drying protocol is repeated three times.After the final evaporation step a mixture of dimethyl formamide andacetonitrile (about 1 mL) containing fluorophilic tosylate 34 (2 mg) isadded and the vial is sealed. The reaction mixture is stirred and heatedat 100° C. for 10 minutes and then is cooled to room temperature. Theproduct mixture comprising the starting tosylate 34 and the product F-18alpha-fluoroalkyl protected dihydrotetrabenazine intermediate isconcentrated under a stream of nitrogen and the residue is dissolved inethanol containing HCl and the mixture is warmed briefly to effectremoval of the THP protecting group. Excess octadecyl amine (5 mg) andpotassium carbonate (2 mg) are then added and the mixture is heated for5 minutes at 60° C. to convert unreacted tosylate groups to thecorresponding octadecyl amine. The product mixture is then diluted withwater (10 mL) and applied to a Sep-Pak cartridge. The cartridge is thenwashed with water (3×) to remove unreacted fluoride ion and other watersoluble components of the product mixture. The radiolabledalpha-fluoroalkyl compound 36 and the corresponding octadecyl amineadduct 37 are then eluted from the cartridge with acetonitrile. Most ofthe acetonitrile is then evaporated and the residue is dissolved inaqueous acetonitrile and subjected to preparative reverse phase HPLC toprovide purified PET imaging agent 36.

Measurement of Binding Affinity of Alpha-Fluoroalkyl Compounds 31, 32,2-epi-32, (+)DTBZ 18, and Fluoroalkyl Tetrabenazine Carbinol Compounds38 and 39 to VMAT-2

VMAT-2 binding affinities were measured for alpha-fluoroalkyldihydrotetrabenazine compounds 31, 32, 2-epi-32 (+)DTBZ 18, andfluoroalkyl tetrabinazine carbinol compound 39 each of which bears afree hydroxyl group at ring position-2 (See Entries 9a-d and 9f of Table9). In addition, the VMAT-2 binding affinity of a fluoroalkyltetrabinazine carbinol compound 38 bearing an acetoxy group at ringposition-2 was also measured. VMAT-2 binding affinity measurements werecarried out by Novascreen Biosciences Corporation (Hanover, Md., USA)using protocol Cat. No. 100-0751. Novascreen, Inc. is a commercialprovider of biological assays for the pharmaceutical industry. Bindingaffinity data are presented in Table 9 and illustrate very high bindingaffinity for the alpha-fluoroalkyl compounds 31, 2-epi-32, and 32relative to a (+)-DTBZ control (Compound 18) and somewhat lower yetstill robust binding activity for fluoroalkyl tetrabinazine carbinolcompounds 38 and 39. The data obtained for alpha-fluoroalkyl compounds31, 32 and 2-epi-32 reveal an unexpected tolerance of fluoroalkylsubstitution at ring position-3, a structural change relative to TBZ andDTBZ which combines a change in the size and lipophilicity of the groupat ring position-3 with the uncertainty which arises whenever a hydrogenin a biologically active molecule is replaced by fluorine. In addition,the binding constants Ki expressed in nano-molar (nM) concentrationunits indicate a very high affinity of the alpha-fluoroalkyl compoundsof the present invention for the VMAT-2 biomarker. The data obtained forfluoroalkyl tetrabenazine carbinol compounds 38 and 39 illustrate asimilar structure-activity principle, namely an unexpected tolerance offluoroalkyl substitution at ring position-2, as well as the unexpectedtolerance for substitution at the hydroxy group at ring position-2. Theensemble of the VMAT-2 binding data gathered for compounds 31, 32 and2-epi-32 with the VMAT-2 binding data gathered for compounds 38 and 39supports the proposition that alpha-fluoroalkyl dihydrotetrabenazinecompounds having structure I and provided by the present invention willalso bind to VMAT-2 and serve as useful positron emission tomography(PET) imaging agents in studies targeting the VMAT-2 biomarker.

TABLE 9 VMAT-2 Binding Affinity of Alpha-Fluoroalkyl Compounds 31, 32and 2-epi-32, (+) DTBZ 18, and Fluoroalkyl Tetrabenazine CarbinolCompounds 38 and 39 Compound Entry No. Structure Ki (nM) 9a 31

6.4 9b 2-epi-32

2.6 9c 32

0.45 9d (+)-DTBZ (18)

3.0 9e 38

19 9f 39

19

Example 3 Preparation of(2R,3R,11bR)-3-(4-fluoro-2,2-dimethylbutyl)-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ylacetate 40

To a solution of 10 mg (27 μmol) of alpha-fluoroalkyldyhydrotetrabenazine compound 32 in 250 μL of anhydrous dichloromethaneat 0° C. is added 4.4 μL (2 equiv., 54 μmol) of anhydrous pyridinefollowed by 3.1 μL (1.2 equiv., 32.4 μmol) of acetic anhydride. Thereaction mixture is allowed to continue stirring, slowly warming to roomtemperature over 14 h. The progress of the reaction is followed byHPLC-MS. The reaction mixture is then quenched by the addition of 1 mLof saturated aqueous ammonium chloride solution and then diluted with anadditional 750 μL of dichloromethane. The aqueous and organic layers arepartitioned and separated, and the aqueous layer is extracted with twoadditional 1 mL portions of dichloromethane. The combined organicextracts are washed with 3 mL of brine, dried (MgSO₄), filtered, andconcentrated under reduced pressure to provide crude alpha-fluoroalkyldihydrotetrabenazine acetate 40 that may be purified by preparativereversed phase HPLC.

Example 4(2R,3R,11bR)-3-(4-fluoro-2,2-dimethylbutyl)-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ylisobutyrate 41

To a solution of 10 mg (27 μmol) of alpha-fluoroalkyldyhydrotetrabenazine compound 32 in 250 μL of anhydrous dichloromethaneat 0° C. is added 4.4 μL (2 equiv., 54 μmol) of anhydrous pyridinefollowed by 5.4 μL (1.2 equiv., 32.4 μmol) of isobutyric anhydride. Thereaction mixture is allowed to continue stirring, slowly warming to roomtemperature over 14 h. The progress of the reaction is followed byHPLC-MS. The reaction mixture is then quenched by the addition of 1 mLof saturated aqueous ammonium chloride solution and then diluted with anadditional 750 μL of dichloromethane. The aqueous and organic layers arepartitioned and separated, and the aqueous layer is extracted with twoadditional 1 mL portions of dichloromethane. The combined organicextracts are washed with 3 mL of brine, dried (MgSO₄), filtered, andconcentrated under reduced pressure to provide crude alpha-fluoroalkyldihydrotetrabenazine isobutyrate 41 that may be purified by preparativereversed phase HPLC.

Example 5 (2R,3R,11bR)-3-(4-fluoro-2,2-dimethylbutyl)-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ylbenzylcarbamate 42

To a solution of 10 mg (27 μmol) of alpha-fluoroalkyldyhydrotetrabenazine compound 32 in 250 μL of anhydrous dichloromethaneat 0° C. is added 4.4 μL (2 equiv., 54 μmol) of anhydrous pyridinefollowed by 4.0 μL (1.2 equiv., 32.4 μmol) of benzyl isocyanate. Thereaction mixture is allowed to continue stirring, slowly warming to roomtemperature over 14 h. The progress of the reaction is followed byHPLC-MS. The reaction mixture is then quenched by the addition of 1 mLof saturated aqueous ammonium chloride solution and then diluted with anadditional 750 μL of dichloromethane. The aqueous and organic layers arepartitioned and separated, and the aqueous layer is extracted with twoadditional 1 mL portions of dichloromethane. The combined organicextracts are washed with 3 mL of brine, dried (MgSO₄), filtered, andconcentrated under reduced pressure to provide crude alpha-fluoroalkyldihydrotetrabenazine N-benzylcarbamate 42 that may be purified bypreparative reversed phase HPLC.

Example 6(2R,3R,11bR)-3-(4-fluoro-2,2-dimethylbutyl)-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ylcarbamate 43

A suspension of triphosgene (3.9 mg, 13.2 μmol) in 150 μL of carbontetrachloride and 2.6 μL (1.2 equiv., 32.4 μmol) of anhydrous pyridineis added to a stirred solution of 10 mg (27 μmol) of alpha-fluoroalkyldyhydrotetrabenazine compound 32 in 150 μL of carbon tetrachloride. Theresulting solution is stirred in a sealed vessel at 55-60° C. for 6 h.Following the allotted time the reaction mixture is cooled to roomtemperature, and the mixture is diluted with 250 μL of dichloromethane.The mixture is washed with two 200 μL portions of water and one 200 μLportion of brine, dried (Na₂SO₄), and concentrated under reducedpressure to provide the crude chloroformate. The crude material isdissolved in 60 μL of THF and is cooled in an ice bath. To this solutionis added 60 μL of a 50% aqueous ammonia solution with vigorous stirring.The reaction mixture is allowed to continue stirring, slowly warming toroom temperature over 14 h. Excess ammonia is removed under a stream ofdry nitrogen. The residue is taken up in 2 mL of dichloromethane andwashed with 1 mL of brine. The organic layer is collected, and theaqueous layer is washed with an additional 1 mL portion ofdichloromethane. The organic extracts are, dried (Na₂SO₄), andconcentrated under reduced pressure to provide crude alpha-fluoroalkyldihydrotetrabenazine carbamate 43 that may be purified by preparativereversed phase HPLC.

Example 7 Preparation of PET Imaging Agent 45

To a Teflon-lined reaction vial contained in a shielded hood and fittedwith a nitrogen purge inlet and magnetic spin bar, is added about 1milliliter of an aqueous acetonitrile solution F-18 fluoride ion,potassium carbonate (about 1 mg), and Kryptofix 221 (about 10 mg). Thevial is heated at 100° C. under a stream of nitrogen to effect theazeotropic removal of water. Additional dry acetonitrile (1 mL) is addedand evaporated. This azeotropic drying protocol is repeated three times.After the final evaporation step a mixture of dimethyl formamide andacetonitrile (about 1 mL) containing fluorophilic acetate-protected DTBZtosylate 44 (2 mg) is added and the vial is sealed. The reaction mixtureis stirred and heated at 100° C. for 10 minutes and then is cooled toroom temperature. The product mixture comprising the starting tosylate44 and the intermediate F-18 alpha-fluoroalkyl protecteddihydrotetrabenazine is diluted with water (10 mL) and applied to aSep-Pak cartridge. The cartridge is then washed with water (3×) toremove unreacted fluoride ion and other water soluble components of theproduct mixture. The radiolabled PET imaging agent 45 and startingtosylate 44 are then eluted from the cartridge with acetonitrile. Mostof the acetonitrile is then evaporated and the residue is dissolved inacetonitrile, filtered and subjected to preparative reverse phase HPLCto afford an aqueous formulation comprising PET imaging agent 45.(Tosylate 44 may be prepared from compound dihydrotetrabenazine compound23 by acetylation of the free hydroxy group at ring position-2 followedby deprotection of the t-butyldiphenylsilyl (TBDPS) group and tosylationof the resultant primary alcohol.)

The foregoing examples are merely illustrative, serving to illustrateonly some of the features of the invention. The appended claims areintended to claim the invention as broadly as it has been conceived andthe examples herein presented are illustrative of selected embodimentsfrom a manifold of all possible embodiments. Accordingly, it is theApplicants' intention that the appended claims are not to be limited bythe choice of examples utilized to illustrate features of the presentinvention. As used in the claims, the word “comprises” and itsgrammatical variants logically also subtend and include phrases ofvarying and differing extent such as for example, but not limitedthereto, “consisting essentially of” and “consisting of.” Wherenecessary, ranges have been supplied, those ranges are inclusive of allsub-ranges there between. It is to be expected that variations in theseranges will suggest themselves to a practitioner having ordinary skillin the art and where not already dedicated to the public, thosevariations should where possible be construed to be covered by theappended claims. It is also anticipated that advances in science andtechnology will make equivalents and substitutions possible that are notnow contemplated by reason of the imprecision of language and thesevariations should also be construed where possible to be covered by theappended claims.

1. An alpha-fluoroalkyl dihydrotetrabenazine compound having structure I

wherein R¹ is a C₁-C₁₀ fluorinated aliphatic radical; R² is hydrogen ora C₁-C₁₀ aliphatic radical; R³ is hydrogen or a C₁-C₁₀ aliphaticradical; and R⁴ is a C₁-C₁₀ aliphatic radical, a C₃-C₁₀ cycloaliphaticradical, or a C₃-C₁₀ aromatic radical.
 2. The alpha-fluoroalkyldihydrotetrabenazine compound according to claim 1, comprising afluorine-18 atom.
 3. The alpha-fluoroalkyl dihydrotetrabenazine compoundaccording to claim 1, comprising a fluorine-19 atom.
 4. Thealpha-fluoroalkyl dihydrotetrabenazine compound according to claim 1,which comprises a mixture of diastereomers.
 5. The alpha-fluoroalkyldihydrotetrabenazine compound according to claim 1, which isenantiomerically enriched.
 6. The enantiomerically enrichedalpha-fluoroalkyl dihydrotetrabenazine compound according to claim 5comprising a principal component enantiomer having structure II

wherein R¹ is a C₁-C₁₀ fluorinated aliphatic radical; R² is hydrogen ora C₁-C₁₀ aliphatic radical; R³ is hydrogen or a C₁-C₁₀ aliphaticradical; and R⁴ is a C₁-C₁₀ aliphatic radical, a C₃-C₁₀ cycloaliphaticradical, or a C₃-C₁₀ aromatic radical.
 7. The enantiomerically enrichedalpha-fluoroalkyl dihydrotetrabenazine compound according to claim 6,which is at least 80% enantiomerically enriched.
 8. The enantiomericallyenriched alpha-fluoroalkyl dihydrotetrabenazine compound according toclaim 5, wherein R¹ is a C₅-C₁₀ fluoraliphatic radical and R² and R³ aremethoxy groups.
 9. The enantiomerically enriched alpha-fluoroalkyldihydrotetrabenazine compound according to claim 5, comprising afluorine-18 atom.
 10. The enantiomerically enriched alpha-fluoroalkyldihydrotetrabenazine compound according to claim 9, said compound beingcomprised in a formulation suitable for use in PET imaging.
 11. Theenantiomerically enriched alpha-fluoroalkyl dihydrotetrabenazinecompound according to claim 5 comprising a principal componentenantiomer having structure III

wherein R¹ is a C₁-C₁₀ fluorinated aliphatic radical; R² is hydrogen ora C₁-C₁₀ aliphatic radical; R³ is hydrogen or a C₁-C₁₀ aliphaticradical; and R⁴ is a C₁-C₁₀ aliphatic radical, a C₃-C₁₀ cycloaliphaticradical, or a C₃-C₁₀ aromatic radical.
 12. A PET imaging agentcomprising an alpha-fluoroalkyl dihydrotetrabenazine compound havingstructure I

wherein R¹ is a C₁-C₁₀ fluorinated aliphatic radical; R2 is hydrogen ora C₁-C₁₀ aliphatic radical; R³ is hydrogen or a C₁-C₁₀ aliphaticradical; and R⁴ is a C₁-C₁₀ aliphatic radical, a C₃-C₁₀ cycloaliphaticradical, or a C₃-C₁₀ aromatic radical.
 13. The PET imaging agent ofclaim 12 further comprising a salt of compound I.
 14. Analpha-fluoroalkyl dihydrotetrabenazine compound having structure II

wherein R¹ is a C₁-C₁₀ fluorinated aliphatic radical; R² is hydrogen ora C₁-C₁₀ aliphatic radical; R³ is hydrogen or a C₁-C₁₀ aliphaticradical; and the group —OR⁴ is selected from the group consisting ofC₁-C₁₀ aliphatic esters, C₁-C₁₀ aliphatic ethers, and C₁-C₁₀ aliphaticcarbamates.
 15. The alpha-fluoroalkyl dihydrotetrabenazine compoundaccording to claim 14, comprising a fluorine-18 atom.
 16. Thealpha-fluoroalkyl dihydrotetrabenazine compound according to claim 14,comprising a fluorine-19 atom.
 17. The alpha-fluoroalkyldihydrotetrabenazine compound according to claim 14, wherein —OR⁴ isacetate.
 18. The alpha-fluoroalkyl dihdyrotetrabenazine compoundaccording to claim 14, wherein —OR⁴ is methoxy.
 19. Thealpha-fluoroalkyl dihydrotetrabenazine compound according to claim 14,wherein —OR⁴ is a carbamate group.
 20. The alpha-fluoroalkyldihydrotetrabenazine compound according to claim 14, wherein thecarbamate group is OCONH₂.